Xanthine oxidase inhibitor

ABSTRACT

Provided are a xanthine oxidase inhibitor, a drug for improving vascular endothelial function, and an excellent therapeutic or prophylactic drug for diseases associated with xanthine oxidase such as gout, hyperuricaemia, and for diseases associated with vascular endothelial functional disorder containing a compound represented in a formula (I) or the pharmaceutically acceptable salt thereof as an active ingredient.

TECHNICAL FIELD

The present invention relates to a novel use of a novel compound havinga xanthine oxidase inhibitory activity.

BACKGROUND ART

Xanthine oxidase is an enzyme catalyzing the conversion of hypoxanthineto xanthine and further to uric acid in nucleic acid metabolism.

A xanthine oxidase inhibitor inhibits uric acid synthesis to reduce alevel of uric acid in the blood with respect to the action of xanthineoxidase. Thus, a xanthine oxidase inhibitor is effective as atherapeutic agent for hyperuricemia and various diseases caused byhyperuricemia. Moreover, there are gouty arthritis and gouty tophuscalled gout as a clinical condition caused by as a result of depositionof urate crystals after prolonged hyperuricemia. In addition,hyperuricemia is considered to be important as a factor of lifestylediseases associated with obesity, hypertension, dyslipidemia anddiabetes or metabolic syndromes, and recently, it has been clarifiedthat hyperuricemia is a risk factor of renal damage, urinary calculi andcardiovascular diseases by epidemiological studies (guideline for theManagement of Hyperuricemia and Gout, 2nd edition). In addition, axanthine oxidase inhibitor is expected to be useful for a treatment ofdiseases related to reactive oxygen species by its inhibitory activityon reactive oxygen species generation, for example, a treatment ofcardiovascular diseases through improvement of endothelial function(Circulation. 2006; 114:2508-2516).

Allopurinol and febuxostat are clinically used as a therapeutic agentfor hyperuricemia, but allopurinol has been reported to have a sideeffect such as Stevens-Johnson syndrome, toxic epidermal necrolysis,hepatic disorder and renal dysfunction (Nippon Rinsho, 2003; 61, Suppl.1: 197-201).

As a compound having a xanthine oxidase inhibitory activity, forexample, a 2-phenylthiazole derivative is reported (Patent Documents 1to 3).

On the other hand, in Patent Documents 4 and 5, a dithiazole carboxylicacid derivative having a benzene ring in the center is reported.Further, in Patent Documents 6 and 7, a biphenyl thioazole carboxylicacid derivative is reported.

PRIOR ART DOCUMENTS Patent Documents

Patent Document 1: International Publication No. 92/09279

Patent Document 2: Japanese Patent Laid-Open No. 2002-105067

Patent Document 3: International Publication No. 96/31211

Patent Document 4: International Publication No. 2011/139886

Patent Document 5: International Publication No. 2011/101867

Patent Document 6: International Publication No. 2010/018458

Patent Document 7: International Publication No. 2010/128163

SUMMARY OF INVENTION Technical Problem

An object of the present invention is to provide a novel compound havinga xanthine oxidase inhibitory activity.

Solution to Problem

As a result of earnest studies, the present inventors have found that acompound represented by the following formula (I):

that is, a compound which has a benzene structure having 3 substituentsand is an azole benzene derivative having a 2-thiazole ring at aposition 1 and a 1,3-nitrogen-containing azole ring at a position 3 isuseful for a xanthine oxidase inhibitory agent and a drug for improvingvascular endothelial function, and completed the present invention. Inaddition, the present inventors have found that the azole benzenederivative may serve as a favorable therapeutic or prophylactic agentfor diseases associated with xanthine oxidase such as gout,hyperuricemia, tumor lysis syndrome, urinary calculi, hypertension,dyslipidemia, diabetes, kidney diseases such as diabetic nephropathy,respiratory diseases such as chronic obstructive pulmonary disease,inflammatory bowel diseases and autoimmune diseases, and diseasesassociated with the vascular endothelial functional disorder such asarteriosclerosis, myocardial infarction, cerebral infarction,cerebrovascular dementia, and completed the present invention.

That is, the present invention is a xanthine oxidase inhibitorcomprising a compound represented by the following formula (I) or apharmaceutically acceptable salt thereof as an active ingredient:

[wherein,

R₁ represents OR, NRR′ which may form a ring or SR, in which R and R′independently represent a hydrogen atom, an alkyl group having 1 to 8carbon atoms optionally substituted with one or a plurality of alkoxygroups having 1 to 8 carbon atoms, halogen atoms or hydroxyl groups, oran aryl group optionally substituted with one or a plurality of alkylgroups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8 carbonatoms or halogen atoms, or a heteroaryl group optionally substitutedwith one or a plurality of alkyl groups having 1 to 8 carbon atoms,alkoxy groups having 1 to 8 carbon atoms or halogen atoms.

R₂ represents a hydrogen atom or an alkyl group having 1 to 8 carbonatoms.

X₁, X₂ and X₃ are independently CR₃ or a nitrogen atom, or X₁ is CR₃ ora nitrogen atom, and X₂ and X₃ together form a benzene ring, in which R₃is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.]

Also, the present invention is a therapeutic agent or a prophylacticagent for diseases associated with xanthine oxidase, which contains acompound represented by the formula (I) or a pharmaceutically acceptablesalt thereof as an active ingredient.

Also, the present invention is an agent for improving vascularendothelial function containing a compound represented by the formula(I) or a pharmaceutically acceptable salt thereof as an activeingredient.

Also, the present invention is a therapeutic agent or a prophylacticagent for diseases associated with vascular endothelial functiondisorder containing a compound represented by the formula (I) or apharmaceutically acceptable salt thereof as an active ingredient.

Advantageous Effects of Invention

The present invention provides a novel use for a novel compound having axanthine oxidase inhibitory activity. In addition, a compound of thepresent invention is useful as a xanthine oxidase inhibitory drug, adrug for improving vascular endothelial function, a therapeutic agent ora prophylactic agent for diseases associated with xanthine oxidase suchas gout, hyperuricemia, tumor lysis syndrome, urinary calculi,hypertension, dyslipidemia, diabetes, kidney diseases such as diabeticnephropathy, respiratory diseases such as chronic obstructive pulmonarydisease, inflammatory bowel disease, autoimmune disease, and diseasesassociated with a vascular endothelial functional disorder such asarteriosclerosis, myocardial infarction, cerebral infarction andcerebrovascular dementia.

DESCRIPTION OF EMBODIMENTS

The terms used singly or in combination in the present description willbe explained in the following. Unless otherwise specified, explanationof each substituent shall be common to each position. In addition, ifany variables exist in an optional constituent factor in an arbitraryconstituent element, the definition is independent in each ofconstituent elements. Further, a combination of substituents andvariables is allowed as long as such a combination results in achemically stable compound.

Generally “xanthine oxidase” is used as a broad sense, enzymescatalyzing oxidative reactions of hypoxanthine to xanthine and furtherto uric acid, and a narrow sense, oxidase-type xanthine oxidoreductasewhich is one of the enzymes catalyzing the reactions, however, in thepresent invention, “xanthine oxidase” collectively means enzymescatalyzing oxidative reactions of hypoxanthine to xanthine and furtherto uric acid, unless otherwise noted. Xanthine oxidoreductase whichcatalyzes such reactions has two types, i.e. oxidase-type anddehydrogenase-type. Both types are included in the “xanthine oxidase” ofthe present invention. In “xanthine oxidase inhibitory activity”,“xanthine oxidase inhibitor” and the like, “xanthine oxidase” has samemeanings as defined above, unless otherwise noted.

In the present invention, the term “a halogen atom” means a fluorineatom, a chlorine atom, a bromine atom, or an iodine atom.

In the present invention, the term “an alkyl group” means a monovelentsaturated linear, cyclic or branched aliphatic hydrocarbon group.Examples of “an alkyl group having 1 to 8 carbon atoms” include methylgroup, ethyl group, n-propyl group, n-butyl group, n-pentyl group,n-hexyl group, isopropyl group, isobutyl group, s-butyl group, t-butylgroup, isopentyl group, 2-methylbutyl group, neopentyl group,1-ethylpropyl group, 4-methylpentyl group, 3-methylpentyl group,2-methylpentyl group, 1-methylpentyl group, 3,3-dimethylbutyl group,2,2-dimethylbutyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutylgroup, 1,3-dimethylbutyl group, 2,3-dimethylbutyl group, 1-ethylbutylgroup, 2-ethylbutyl group, t-pentyl group, isohexyl group, cyclopropylgroup, cyclobutyl group, cyclopentyl group, cyclohexyl group,cycloheptyl group, cyclopropylmethyl group, cyclobutylmethyl group,cyclopentylmethyl group, cyclohexylmethyl group, cycloheptylmethyl groupand the like. Examples of “an alkyl group having 1 to 3 carbon atoms”include methyl group, ethyl group, n-propyl group, and isopropyl group.

In the present invention, the term “an alkoxy group having” means amonovelent saturated liner, cyclic or branched aliphatic hydrocarbon oxygroup. Examples of “an alkoxy group having 1 to 8 carbon atoms” includemethoxy group, ethoxy group, n-propoxy group, n-butoxy group,n-pentyloxy group, n-hexoxy group, isopropoxy group, isobutoxy group,s-butoxy group, t-butoxy group, isopentyloxy group, 2-methylbutoxygroup, neopentyloxy group, cyclopropoxy group, cyclobutoxy group,cyclopentyloxy group, cyclohexyloxy group, cycloheptyloxy group,cyclopropylmethoxy group, cyclobutylmethoxy group, cyclopentylmethoxygroup, cyclohexylmethoxy group and the like.

In the present invention, the term “an aryl group” means a monocyclic orbicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms.Examples of the aryl group include phenyl group, naphthyl group, indenylgroup, tetrahydronaphthyl group, indanyl group, azulenyl group and thelike.

In the present invention, the term “a heteroaryl group” means amonocyclic or bicyclic aromatic heterocyclic group having 1 to 5heteroatoms selected from oxygen atom, sulfer atom, and nitrogen atom.Examples of the heteroaryl group includespyridyl group, pyrazyl group,pyrimidyl group, furyl group, thienyl group, isoxazolyl group,isothiazolyl group, benzofuranyl group, benzothienyl group,benzothiazolyl group, benzoimidazolyl group, benzooxazolyl group,pyranyl group, imidazolyl group, oxazolyl group, thiazolyl group,triazinyl group, triazolyl group, benzoxazolyl group, benzoisoxazolylgroup and the like.

In the present invention, the term “an optionally substituted alkylgroup having 1 to 8 carbon atoms means an alkyl group having 1 to 8carbon atoms which is optionally substituted with one or moresubstituents at substitutable positions. Examples of substituent of thealkyl group having 1 to 8 carbon atoms include alkoxy groups having 1 to8 carbon atoms, halogen atoms and hydroxyl groups. When the number ofthe substituents is plural, the respective substituents may be the sameor different.

In the present invention, the term “an optionally substituted arylgroup” means an aryl group which is optionally substituted with one ormore substituents at substitutable positions. Examples of substituent ofthe aryl group include an alkyl groups having 1 to 8 carbon atoms,alkoxy groups having 1 to 8 carbon atoms and halogen atoms. When thenumber of the substituents is plural, the respective substituents may bethe same or different.

In the present invention, the term “an optionally substituted heteroarylgroup” means a heteroaryl group which is optionally substituted with oneor more substituents at substitutable positions. Examples of substituentof the heteroaryl group include an alkyl groups having 1 to 8 carbonatoms, alkoxy groups having 1 to 8 carbon atoms and halogen atoms. Whenthe number of the substituents is plural, the respective substituentsmay be the same or different.

In the present invention, the term “a protective group of a carboxylgroup” is, for example, a general protective group of a carboxyl group,which is described in PROTECTIVE GROUPS in ORGANIC SYNTHESIS, THIRDEDITION, H John Wiley & Sons, Inc. and examples of the protective groupinclude methyl group, ethyl group, isopropyl group, heptyl group,t-butyl group, methoxymethyl group, methylthiomethyl group,methoxyethoxymethyl group, methoxyethyl group, benzyl group and thelike.

In the present invention, the term “a protective group of a phenolichydroxyl group” is, for example, a general protective group of aphenolic hydroxyl group, which is described in PROTECTIVE GROUPS inORGANIC SYNTHESIS, THIRD EDITION, H John Wiley & Sons, Inc. and examplesof the protective group include methyl group, isopropyl group, allylgroup, t-butyl group, methoxymethyl group, methylthiomethyl group,methoxyethoxymethyl group, 1-ethoxyethyl group, benzyl group,4-methoxybenzyl group, acetyl group, trimethylsilyl group,t-butyldimethylsilyl group and the like.

In the above formula (I), R₁ represents OR, NRR′ which may form a ringor SR. Here, R and R′ independently represent a hydrogen atom, an alkylgroup having 1 to 8 carbon atoms optionally substituted with one or aplurality of alkoxy groups having 1 to 8 carbon atoms, halogen atoms orhydroxyl groups, an aryl group optionally substituted with one or aplurality of alkyl groups having 1 to 8 carbon atoms, alkoxy groupshaving 1 to 8 carbon atoms or halogen atoms, or a heteroaryl groupoptionally substituted with one or a plurality of alkyl groups having 1to 8 carbon atoms, an alkoxy groups having 1 to 8 carbon atoms or ahalogen atom. R₁ is preferably OR. When R₁ is OR or SR, R is preferablyan alkyl group having 1 to 8 carbon atoms optionally substituted withone or a plurality of alkoxy groups having 1 to 8 carbon atoms, halogenatoms or hydroxyl groups, or an aryl group optionally substituted withone or a plurality of alkyl groups having 1 to 8 carbon atoms, alkoxygroups having 1 to 8 carbon atoms, halogen atoms. More preferably, R isan alkyl group having 1 to 8 carbon atoms optionally substituted withone or a plurality of alkoxy groups having 1 to 8 carbon atoms orhydroxyl groups. Particularly preferably, R is an isopropyl group, anisobutyl group or a neopentyl group. In NRR′ in which R₁ may form aring, the term “NRR′ forms a ring” means that R and R′ are bonded toform a saturated nitrogen-containing ring. In the case of NRR′ in whichR₁ may form a ring, preferably R and R′ are independently an alkyl grouphaving 1 to 8 carbon atoms optionally substituted with a hydroxyl group,and more preferably R and R′ are independently a methyl group, an ethylgroup or an isopropyl group, or R and R′ are more preferably bonded toform together a pyrrolidin-1-yl group, a piperidin-1-yl group or amorpholin-1-yl group.

In the above formula (I), R₂ represents a hydrogen atom or an alkylgroup having 1 to 8 carbon atoms. Specific examples of the term “analkyl group having 1 to 8 carbon atoms” are the same as the definitiondescribed above. R₂ is preferably a hydrogen atom or an alkyl grouphaving 1 to 3 carbon atoms and specific examples of the alkyl groupinclude a methyl group, an ethyl group, an n-propyl group and anisopropyl group, more preferably a hydrogen atom or a methyl group, andparticularly preferably a methyl group.

In the above formula (I), X₁, X₂ and X₃ are independently a CR₃ or anitrogen atom, or X₁ is CR₃ or a nitrogen atom and X₂ and X₃ togetherform a benzene ring. R₃ represents a hydrogen atom or an alkyl grouphaving 1 to 8 carbon atoms. If X₁ is CR₃ or a nitrogen atom and X₂ andX₃ together form a benzene ring, the compound may be represented byfollowing structural formula:

X₁, X₂ and X₃ are preferably independently CR₃ or a nitrogen atom. Amore preferable combination is that X₁ is a nitrogen atom, X₂ is CR₃ ora nitrogen atom and X₃ is CR₃. In any of the combinations, R₃ ispreferably a hydrogen atom. If X₁ is a nitrogen atom, X₂ is CH or anitrogen atom and X₃ is CH, the compound may be represented by followingstructural formula:

In the above formula (I), in any of the cases where R₁ is OR, NRR′ whichmay form a ring or SR, a preferable combination of R, R′, R₂, X₁, X₂ andX₃ is that preferable groups described above individually are combined,in which R₃ is a hydrogen group or an alkyl group having 1 to 8 carbonatoms. In the preferable combination of R, R′, R₂, X₁, X₂ and X₃, R₃ ismore preferably a hydrogen atom.

A more preferable combination of R, R′, R₂, X₁, X₂ and X₃ is the one inwhich more preferable groups are combined, in which R₃ is a hydrogenatom or an alkyl group having 1 to 8 carbon atoms. In the morepreferable combination of R, R′, R₂, X₁, X₂ and X₃, R₃ is morepreferably a hydrogen atom.

A further more preferable combination of R, R′, R₂, X₁, X₂ and X₃ isthat R is an isopropyl group, an isobutyl group or a neopentyl group, R₂is a methyl group, X₁ is a nitrogen atom, X₂ is CR₃ or a nitrogen atomand X₃ is CR₃, in which R₃ is a hydrogen atom.

In any of combinations of a more preferable combination and a furthermore preferable combination of R, R′, R₂, X₁, X₂ and X₃, R₁ ispreferably OR.

Specific examples of the preferable combination of R₁, R, R′, R₂, X₁, X₂and X₃ in the formula (I) of the present invention include the followingcombinations 1) to 9):

1) R₁ is OR; R is an alkyl group having 1 to 8 carbon atoms optionallysubstituted with one or a plurality of alkoxy groups having 1 to 8carbon atoms, halogen atoms or hydroxyl groups, or an aryl groupoptionally substituted with one or a plurality of alkyl groups having 1to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms or halogenatoms; R₂ is a hydrogen atom or an alkyl group having 1 to 3 carbonatoms; X₁ is a nitrogen atom; X₂ is CR₃ or a nitrogen atom; X₃ is CR₃;and R₃ is a hydrogen atom;2) R₁ is OR; R is an alkyl group having 1 to 8 carbon atoms optionallysubstituted with one or a plurality of alkoxy groups having 1 to 8carbon atoms or hydroxyl groups; R₂ is a hydrogen atom or an alkyl grouphaving 1 to 3 carbon atoms; X₁ is a nitrogen atom; X₂ is CR₃ or anitrogen atom; X₃ is CR₃; and R₃ is a hydrogen atom;3) R₁ is OR; R is an isopropyl group, an isobutyl group or a neopentylgroup; R₂ is a hydrogen atom or a methyl group; X₁ is a nitrogen atom;X₂ is CR₃ or a nitrogen atom; X₃ is CR₃; and R₃ is a hydrogen atom;4) R₁ is SR; R is an alkyl group having 1 to 8 carbon atoms optionallysubstituted with one or a plurality of alkoxy groups having 1 to 8carbon atoms, halogen atoms or hydroxyl groups, or an aryl groupoptionally substituted with one or a plurality of alkyl groups having 1to 8 carbon atoms, alkoxy groups having 1 to 8 carbon atoms or halogenatoms; R₂ is a hydrogen atom or an alkyl group having 1 to 3 carbonatoms; X₁ is a nitrogen atom; X₂ is CR₃ or a nitrogen atom; X₃ is CR₃;and R₃ is a hydrogen atom;5) R₁ is SR; R is an alkyl group having 1 to 8 carbon atoms optionallysubstituted with one or a plurality of alkoxy groups having 1 to 8carbon atoms or hydroxyl groups; R₂ is a hydrogen atom or an alkyl grouphaving 1 to 3 carbon atoms; X₁ is a nitrogen atom; X₂ is CR₃ or anitrogen atom; X₃ is CR₃; and R₃ is a hydrogen atom;6) R₁ is SR; R is an isopropyl group, an isobutyl group or a neopentylgroup; R₂ is a hydrogen atom or a methyl group; X₁ is a nitrogen atom;X₂ is CR₃ or a nitrogen atom; X₃ is CR₃; and R₃ is a hydrogen atom;7) R₁ is NRR′ which may form a ring; R and R′ are independently an alkylgroup having 1 to 8 carbon atoms optionally substituted with one or aplurality of alkoxy groups having 1 to 8 carbon atoms or hydroxylgroups; R₂ is a hydrogen atom or an alkyl group having 1 to 3 carbonatoms; X₁ is a nitrogen atom; X₂ is CR₃ or a nitrogen atom; X₃ is CR₃;and R₃ is a hydrogen atom;8) R₁ is NRR′ which may form a ring; R and R′ are independently a methylgroup, an ethyl group or an isopropyl group or R and R′ are bonded toform together a pyrrolidin-1-yl group, a piperidin-1-yl group or amorpholin-1-yl group; R₂ is a hydrogen atom or an alkyl group having 1to 3 carbon atoms; X₁ is a nitrogen atom; X₂ is CR₃ or a nitrogen atom;X₃ is CR₃; and R₃ is a hydrogen atom;9) R₁ is NRR′ which may form a ring; R and R′ are independently a methylgroup, an ethyl group or an isopropyl group or R and R′ are bonded toform together a pyrrolidin-1-yl group, a piperidin-1-yl group or amorpholin-1-yl group; R₂ is a hydrogen atom or a methyl group; X₁ is anitrogen atom; X₂ is a CR₃ or a nitrogen atom; X₃ is CR₃; and R₃ is ahydrogen atom.

A compound of the present invention is a compound exhibiting anexcellent xanthine oxidase inhibitory activity. In addition, a compoundof the present invention has an excellent uric acid lowering effect.Further, a compound of the present invention has a sustained uric acidlowering effect over a long period of time.

Examples of a preferred compound include the following compounds.

Compound No. Structure Name 1

2-[3-(1H-imidazol-1-yl)-4-(2- methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 2

2-[4-(2,2-dimethylpropoxy)-3- (1H-imidazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 3

2-[4-(cyclobutylmethoxy)-3- (1H-imidazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 4

2-[4-(cyc1opentylmethoxy)-3- (1H-imidazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 5

2-[4-(cyclopentyloxy)-3-(1H- imidazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 6

2-[4-(cyclohexyloxy)-3-(1H- imidazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 7

2-[3-(1H-imidazol-1-yl)-4- phenoxyphenyl]-4-methyl-1,3-thiazole-5-carboxylic acid 8

2-[4-(2-fluorophenoxy)-3-(1H- imidazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 9

4-methyl-2-[3-(2-methyl-1H- imidazol-1-yl)-4-(2-methylpropoxy)phenyl]-1,3- thiazole-5-carboxylic acid 10

4-methyl-2-[3-(5-methyl-1H- 4-tetrazol-1-yl)-4-(2-methylpropoxy)phenyl]-1,3- thiazole-5-carboxylic acid 11

2-[3-(1H-1,3-benzodiazol-1-yl)- 4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 12

4-methyl-2-[3-(3-methyl-1H- 1,2,4-triazol-1-yl)-4-(2-methylpropoxy)phenyl]-1,3- thiazole-5-carboxylic acid 13

4-methyl-2-[4-(2- methylpropoxy)-3-(1H-1,2,4- triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid 14

4-methyl-2-[3-(5-methyl-1H- 1,2,4-triazol-1-yl)-4-(2-methylpropoxy)phenyl]-1,3- thiazole-5-carboxylic acid 15

4-methyl-2-[4-phenoxy-3-(1H- 1,2,4-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid 16

4-methyl-2-[4-(propan-2-yloxy)- 3-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5- carboxylic acid 17

4-methyl-2-[4-(2- methylpropoxy)-3-(1H-1,2,3- triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid 18

2-[4-(2,2-dimethylpropoxy)-3- (1H-1,2,3-triazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 19

2-[4-(cyclobutylmethoxy)-3- (1H-1,2,3-triazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 20

2-[4-(propan-2-yloxy)-3-(1H- 1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid 21

2-[4-(2-methylpropoxy)-3-(1H- 1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid 22

4-methyl-2-[4-phenoxy-3-(1H- 1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid 23

2-[4-(2-fluorophenoxy)-3-(1H- 1,2,3-triazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 24

4-methyl-2-[4-(propan-2-yloxy)- 3-(1H-1,2,3,4-tetraazole-1-yl)phenyl]-1,3-thiazole-5- carboxylic acid 25

4-methyl-2-[4-(2- methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3- thiazole-5-carboxylic acid 26

2-[4-(2,2-dimethylpropoxy)-3- (1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3- thiazole-5-carboxylic acid 27

2-[4-(cyclobutylmethoxy)-3- (1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3- thiazole-5-carboxylic acid 28

2-[4-(cyclopentyloxy)-3-(1H- 1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 29

2-[4-(3-hydroxy-2- methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl- 1,3-thiazole-5-carboxylic acid 30

2-[4-(2-hydroxy-2- methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl- 1,3-thiazole-5-carboxylic acid 31

2-[4-(propan-2-yloxy)-3-(1H- 1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid 32

2-[4-(2-methylpropoxy)-3-(1H- 1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid 33

4-methyl-2-[4-phenoxy-3-(1H- 1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylic acid 34

2-[4-(2-fluorophenoxy)-3-(1H- 1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 35

2-[4-(2-methoxyphenoxy)-3- (1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3- thiazole-5-carboxylic acid 36

2-[4-(2,6-difluorophenoxy)-3- (1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3- thiazole-5-carboxylic acid 37

2-[4-(3-fluotophenoxy)-3-(1H- 1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 38

2-[4-(3-methylphenoxy)-3-(1H- 1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 39

2-[4-(2-chlorophenoxy)-3-(1H- 1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 40

2-[4-(4-fluoro-3- methylphenoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl- 1,3-thiazole-5-carboxylic acid 41

2-[4-(4-fluoro-2- methylphenoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl- 1,3-thiazole-5-carboxylic acid 42

2-[4-(2,4-difluorophenoxy)-3- (1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3- thiazole-5-carboxylic acid 43

2-[4-(2-fluoro-6- methoxyphenoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4- methyl-1,3-thiazole-5- carboxylic acid44

2-[4-(2-methylphenoxy)-3-(1H- 1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 45

2-[4-(4-methylphenoxy)-3-(1H- 1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 46

2-[4-(3-fluoro-5- methylphenoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl- 1,3-thiazole-5-carboxylic acid 47

2-[4-(2,5-difluorophenoxy)-3- (1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3- thiazole-5-carboxylic acid 48

2-[4-(2-fluoro-5- methylphenoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl- 1,3-thiazole-5-carboxylic acid 49

4-methyl-2-{4-[(2- methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}- 1,3-thiazole-5-carboxylic acid 50

4-methyl-2-[4-(propan-2- ylsulfanyl)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3- thiazole-5-carboxylic acid 51

4-methyl-2-{4-[(4- methylphenyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}- 1,3-thiazole 5-carboxylic acid 52

2-[4-(N,N-diethylamino)-3-(1H- 1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5- carboxylic acid 53

4-methyl-2-[4-(pyrrolidin-1-yl)- 3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole 5- carboxylic acid

Among these compounds, preferred compounds are compounds Nos. 1, 2, 3,4, 5, 6, 9, 10, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24, 25, 26, 27,28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52 and 53, more preferred compounds are compoundNos. 1, 9, 11, 12, 13, 14, 16, 17, 18, 19, 20, 21, 24, 25, 26, 27, 28,29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52 and 53, and particularly preferred compounds arecompounds Nos 17, 24, 25 and 26.

In the compounds represented by the formula (II), which may be used asthe manufacturing intermediates of the compounds represented by theformula (I) of the present invention, R1, R, R′, R2, X1, X2, X3 and CR3are the same as the definition in the formula (I). R4 represents aprotective group of a carboxyl group. The definition of the protectivegroup of a carboxyl group is as described above and preferably is amethyl group, an ethyl group or a benzyl group.

<General Synthesis Methods>

The compounds of the formula (I) thereof may be synthesized, forexample, according to any of the synthesis methods described below. Inaddition, in each of the formulas, R₁, R, R′, R₂, X₁, X₂ and X₃ are thesame as defined in the formula (I). Further, the reagents or solvents orthe like as the conditions described in the chemical formulas are onlyexemplified as described in the text. Each of the substituents may beprotected by a suitable protective group or may be deprotected in asuitable stage, where necessary. In addition, as a suitable protectivegroup and a method for removing the protective group, a protective groupof each substituent widely used in this field and a well-known methodmay be employed and are described, for example, in PROTECTIVE GROUPS inORGANIC SYNTHESIS, THIRD EDITION, John Wiley&Sons, Inc.

Synthesis of Compound (A-2)

(wherein Y₁ and Y₂ represent a leaving group.) Examples of a leavinggroup represented by Y₁ and Y₂ include a halogen atom, amethanesulfonyloxy group, a p-toluenesulfonyloxy group, atrifluoromethanesulfonyloxy group and the like. The reaction is a methodfor synthesizing a compound (A-2) by reacting a phenolic hydroxyl groupin the compound (A-1) with an alkylating reagent having a leaving groupunder the presence of a base. Examples of the base to be used include aninorganic salt such as sodium hydride, sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, potassium carbonate andcesium carbonate, a metal alkoxide such as sodium ethoxide, sodiummethoxide and potassium t-butoxide and an organic amine such astriethylamine, pyridine, 4-aminopyridine, N-ethyl-N,N-diisopropylamine(DIPEA) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). The reaction isperformed by reacting the compound (A-1) with an equivalent or slightlyexcessive amount of a base in a solvent inactive to the reaction at 0°C. to 140° C., followed by adding an equivalent amount or an excessiveamount of an alkylating reagent to allow the reaction to proceedgenerally for 0.5 to 16 hours. The reaction is preferably performedunder an inert gas atmosphere such as nitrogen. Here, the solventincludes, though not particularly limited, for example: ethers such asdiethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethaneand 1,2-diethoxy ethane; N,N-dimethylformamide (DMF);N-methylpyrrolidone; dimethyl sulfoxide (DMSO); water; or a mixedsolvent thereof.

In addition, the compound (A-2) may be synthesized, for example,according to the synthesis method described below.

Synthesis of Compound (A-2)

(wherein Y₁ and Y₃ represent a leaving group.) Examples of a leavinggroup represented by Y₁ and Y₃ include a halogen atom, amethanesulfonyloxy group, a p-toluenesulfonyloxy group and atrifluoromethanesulfonyloxy group. The reaction is a method forsynthesizing a compound (A-2) by converting alcohols to lithiumalkoxide, sodium alkoxide or potassium alkoxide with a base, followed bythe reaction with a compound (A-3). Examples of the base to be usedinclude an inorganic salt such as sodium hydride, sodium hydroxide,potassium hydroxide, lithium hydroxide, sodium carbonate, potassiumcarbonate and cesium carbonate, a metal alkoxide such as sodiumethoxide, sodium methoxide and potassium t-butoxide, and an organicamine such as triethylamine, pyridine, 4-aminopyridine,N-ethyl-N,N-diisopropylamine (DIPEA) and1,8-diazabicyclo[5.4.0]-7-undecene (DBU). The reaction is performed byreacting an equivalent or excessive amount of alcohols with anequivalent or slightly excessive amount of a base at −20° C. to 120° C.in a solvent inactive to the reaction, followed by adding the compound(A-3) to allow the reaction to proceed generally for 0.5 to 16 hours.The reaction is preferably performed under an inert gas atmosphere suchas nitrogen. Here, the solvent includes, though not particularlylimited, for example: aromatic hydrocarbons such as benzene, toluene andxylene; ethers such as diethyl ether, tetrahydrofuran (THF),1,4-dioxane, 1,2-dimethoxy ethane and 1,2-diethoxy ethane;N,N-dimethylformamide (DMF), N-methylpyrrolidone; dimethyl sulfoxide(DMSO); or a mixed solvent thereof.

Synthesis of Compound (A-5)

(wherein Y₁ represents a leaving group.) The reaction is a method forsynthesizing a compound (A-5) by a substitution reaction between thecompounds (A-2) and (A-4). Examples of a leaving group represented by Y₁include a halogen atom, a methanesulfonyloxy group, ap-toluenesulfonyloxy group and a trifluoromethanesulfonyloxy group. Thereaction is performed by reacting the compounds (A-2) and (A-4) in anequivalent amount or using an excessive amount of one of the compoundsunder the presence of a base in a solvent inactive to the reaction atroom temperature to a reflux temperature under heating for generally 0.5hours to 2 days. The reaction is preferably performed under an inert gasatmosphere such as nitrogen. Examples of the base to be used include aninorganic salt such as sodium hydride, sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, potassium carbonate andcesium carbonate, a metal alkoxide such as sodium ethoxide and sodiummethoxide and an organic amine such as triethylamine, pyridine,4-aminopyridine, N-ethyl-N,N-diisopropylamine (DIPEA) and1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Here, the solvent includes,though not particularly limited, for example: aromatic hydrocarbons suchas benzene, toluene and xylene; ethers such as diethyl ether,tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and1,2-diethoxy ethane; halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane and chloroform; N,N-dimethylformamide (DMF);N-methylpyrrolidone, dimethyl sulfoxide (DMSO); or a mixed solventthereof.

Synthesis of Compound (A-6)

The reaction is a conversion reaction from a cyano group to a thioamidegroup and is performed by reacting an aromatic cyano group derivativerepresented by the above formula (A-5) with a sulfur source under acidicconditions. The reaction is performed by using the compound (A-5) andthe sulfur source in an equivalent amount or using an excessive amountof one of the compounds under the presence of an acid in a solventinactive to the reaction at room temperature to a reflux temperatureunder heating for generally 0.5 hours to 2 days. The reaction ispreferably performed under an inert gas atmosphere such as nitrogen.Examples of the sulfur source to be used include hydrogen sulfide,thioacetamide or thioacetic acid. Examples of the acid to be usedinclude inorganic acid such as hydrochloric acid, sulfuric acid andorganic acid such as acetic acid, or an aqueous solution of these acids.Here, the solvent includes, though not particularly limited, forexample: aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane,1,2-dimethoxy ethane and 1,2-diethoxy ethane; N,N-dimethylformamide(DMF); N-methylpyrrolidone; dimethyl sulfoxide (DMSO); or a mixedsolvent thereof.

Synthesis of Compound (A-8)

(wherein R₄ represents a protective group of a carboxyl group and Y₄represents a leaving group.) Examples of a leaving group represented byY₄ include a halogen atom, a methanesulfonyloxy group, ap-toluenesulfonyloxy group and a trifluoromethanesulfonyloxy group. Thereaction is a ring-forming reaction of a thiazole ring and is performedby reacting the compounds (A-6) and (A-7) in an equivalent amount orusing an excessive amount of one of the compounds in a solvent inactiveto the reaction at room temperature to a reflux temperature underheating for generally 0.5 hours to 2 days. In addition, an equivalent orexcessive amount of a base may be added. The reaction is preferablyperformed under an inert gas atmosphere such as nitrogen. Here, thesolvent includes, though not particularly limited, for example: aromatichydrocarbons such as benzene, toluene and xylene; ethers such as diethylether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and1,2-diethoxy ethane; halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane and chloroform; alcohols such as methanol, ethanol,2-propanol and butanol; N,N-dimethylformamide (DMF);N-methylpyrrolidone; dimethylsulfoxide (DMSO); or a mixed solventthereof. Examples of the base to be used include: an inorganic salt suchas sodium hydride, sodium hydroxide, potassium hydroxide, lithiumhydroxide, sodium carbonate, potassium carbonate and cesium carbonate, ametal alkoxide such as sodium ethoxide and sodium methoxide;triethylamine; N-ethyl-N,N-diisopropylamine (DIPEA); and1,8-diazabicyclo[5.4.0]-7-undecene (DBU).

Synthesis of Compound (A-9)

(wherein R₄ represents a protective group of a carboxyl group.) Thesynthesis method is a method for synthesizing a compound (A-9) of thepresent invention by deproteting a protective group R₄ of the compound(A-8) by an acid, a base or the like. The reaction is performed byreacting the compound (A-8) with an equivalent or excessive amount of anacid or a base in a solvent inactive to the reaction at room temperatureto a reflux temperature under heating for generally 0.5 hours to 5 days.Here, the solvent includes, though not particularly limited, forexample: aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane,1,2-dimethoxy ethane and 1,2-diethoxy ethane; halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane and chloroform; alcoholssuch as methanol, ethanol, 2-propanol and butanol; N,N-dimethylformamide(DMF); N-methylpyrrolidone; dimethyl sulfoxide (DMSO); water; or a mixedsolvent thereof. Examples of the acid include an inorganic acid such ashydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid andphosphoric acid; or a solution obtained by diluting these acids withwater or an organic solvent. Examples of the base include an inorganicsalt such as sodium hydroxide, potassium hydroxide, lithium hydroxide,sodium carbonate, potassium carbonate, a metal alkoxide such as sodiumethoxide and sodium methoxide; or a solution obtained by diluting thesebases with water or an organic solvent.

Synthesis of Compound (B-2)

(wherein Y₂ and Y₅ represent a leaving group.) Examples of a leavinggroup represented by Y₂ and Y₅ include a halogen atom, amethanesulfonyloxy group, a p-toluenesulfonyloxy group and atrifluoromethanesulfonyloxy group. The reaction is a method forsynthesizing a compound (B-2) by reacting a phenolic hydroxyl group inthe compound (B-1) with an alkylating reagent having a leaving group inthe presence of a base. Examples of the basic substance to be usedinclude an inorganic salt such as sodium hydride, sodium hydroxide,potassium hydroxide, lithium hydroxide, sodium carbonate, potassiumcarbonate and cesium carbonate, a metal alkoxide such as sodiumethoxide, sodium methoxide and potassium t-butoxide or an organic aminesuch as triethylamine, pyridine, 4-aminopyridine,N-ethyl-N,N-diisopropylamine (DIPEA) and1,8-diazabicyclo[5.4.0]-7-undecene (DBU). The reaction is performed byreacting the compound (B-1) with an equivalent or slightly excessiveamount of a base in a solvent inactive to the reaction at 0° C. to 140°C., followed by adding an equivalent or excessive amount of analkylating reagent to allow the reaction to proceed generally for 0.5 to16 hours. The reaction is preferably performed under an inert gasatmosphere such as nitrogen. Here, the solvent includes, though notparticularly limited, for example: ethers such as diethyl ether,tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and1,2-diethoxy ethane; N,N-dimethylformamide (DMF); N-methylpyrrolidone;dimethyl sulfoxide (DMSO); water; or a mixed solvent thereof.

In addition, the compound (B-2) may be synthesized, for example,according to the synthesis method described below.

Synthesis of Compound (B-2)

(wherein Y₃ and Y₅ represent a leaving group.) Examples of a leavinggroup represented by Y₃ and Y₅ include a halogen atom, amethanesulfonyloxy group, a p-toluenesulfonyloxy group and atrifluoromethanesulfonyloxy group. The reaction is a method forsynthesizing a compound (B-2) by converting alcohols to correspondinglithium derivative, sodium derivative or potassium derivative with abase, followed by the reaction with a compound (B-3). Examples of thebase to be used include an inorganic salt such as sodium hydride, sodiumhydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate,potassium carbonate and cesium carbonate, a metal alkoxide such assodium ethoxide, sodium methoxide and t-potassium butoxide or an organicamine such as triethylamine, pyridine, 4-aminopyridine,N-ethyl-N,N-diisopropylamine (DIPEA) and1,8-diazabicyclo[5.4.0]-7-undecene (DBU). The reaction is performed byreacting an equivalent or excessive amount of alcohols with anequivalent or slightly excessive amount of a base in a solvent inactiveto the reaction at −20° C. to 120° C., followed by the addition of thecompound (B-3) and allowing the reaction to proceed generally for 0.5 to12 hours. The reaction is preferably performed under an inert gasatmosphere such as nitrogen. Here, the solvent includes, though notparticularly limited, for example: aromatic hydrocarbons such asbenzene, toluene and xylene; ethers such as diethyl ether,tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and1,2-diethoxy ethane; N,N-dimethylformamide (DMF); N-methylpyrrolidone;dimethyl sulfoxide (DMSO); or a mixed solvent thereof.

Synthesis of Compound (B-5)

(wherein R₄ represents a protective group of a carboxyl group and Y₅represents a leaving group.) The synthesis method is a method forsynthesizing a compound (B-5) by coupling compounds (B-2) and (B-4).Examples of a leaving group represented by Y₅ include a halogen atom, amethanesulfonyloxy group, a p-toluenesulfonyloxy group and atrifluoromethanesulfonyloxy group. The reaction is performed by reactingthe compounds (B-2) and (B-4) in an equivalent amount or using anexcessive amount of one of the compounds and adding a ligand, acarboxylic acid and a monovalent or divalent copper salt in some cases,under the presence of a base and a transition metal catalyst in asolvent inactive to the reaction at room temperature to a refluxtemperature under heating for generally 0.5 hours to 2 days. Thereaction is preferably performed under an inert gas atmosphere such asnitrogen. Here, the solvent includes, though not particularly limited,for example: aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane,1,2-dimethoxy ethane and 1,2-diethoxy ethane; halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane and chloroform; alcoholssuch as methanol, ethanol, 2-propanol and butanol; N,N-dimethylformamide(DMF); N-methylpyrrolidone; dimethyl sulfoxide (DMSO); water or a mixedsolvent thereof. Examples of the base include: lithium hydride, sodiumhydride, potassium hydride, sodium hydroxide, sodium hydroxide,potassium hydroxide, sodium carbonate, potassium carbonate, cesiumcarbonate, potassium fluoride, cesium fluoride, tripotassium phosphate,sodium acetate and potassium acetate; a metal salt of an alkoxide having1 to 6 carbon atoms (lithium salt, sodium salt, potassium salt andmagnesium salt); a metal salt of an alkyl anion having 1 to 6 carbonatoms (lithium salt, sodium salt, potassium salt and magnesium salt);tetra (alkyl having 1 to 4 carbon atoms) ammonium salt (fluoride,chloride and bromide); diisopropylethylamine; tributylamine;N-methylmorpholine; diazabicycloundecene; diazabicylcooctane; orimidazole. Examples of the transition metal catalyst include copper,palladium, cobalt, iron, rhodium, ruthenium and iridium. Examples of theligand include tri(t-butyl)phosphine, tri(cyclohexyl)phosphine,t-butyldicyclohexylphosphine, di(t-butyl)cyclohexylphosphine ordi(t-butyl)methylphosphine. Examples of the monovalent or divalentcopper salt include copper chloride (I), copper bromide (I), copperiodide (I), copper acetate (I), copper fluoride (II), copper chloride(II), copper bromide (II), copper iodide (II), copper acetate (II), ahydrate thereof and a mixture thereof. Examples of the carboxylic acidinclude formic acid, acetic acid, propionic acid, n-butyric acid,isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid andtrifluoroacetic acid.

Synthesis of Compound (B-6)

(wherein R₄ represents a protective group of a carboxyl group.) Thesynthesis method is a method for synthesizing a compound (B-6) by thereduction of a nitro group of a compound (B-5). The reaction isperformed by reacting the compound (B-5) under a hydrogen gas atmospherein the presence of a transition metal catalyst in a solvent inactive tothe reaction at room temperature to a reflux temperature under heatingfor generally 0.5 hours to 2 days. Here, the solvent includes, thoughnot particularly limited, for example: aromatic hydrocarbons such asbenzene, toluene and xylene; ethers such as diethyl ether,tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and1,2-diethoxy ethane; halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane and chloroform; alcohols such as methanol, ethanol,2-propanol and butanol; N,N-dimethylformamide (DMF);N-methylpyrrolidone; dimethyl sulfoxide (DMSO); ethyl acetate; or amixed solvent thereof. Preferred examples of the transition metalcatalyst include palladium-carbon, palladium hydroxide, palladium black,platinum-carbon, Raney nickel, and the like.

Synthesis of Compound (B-9)

(wherein R₆ represents a methyl group or a p-tolyl group.) The synthesismethod may be referred to HETEROCYCLES, VOL. 48, No. 4, 1998, P695-702.That is, the synthesis method is a method for synthesizing a compound(B-9) by the condensation of compounds (B-7) and (B-8). The reaction isperformed by reacting the compounds (B-7) and (B-8) in an equivalentamount or using an excessive amount of one of the compounds in a solventinactive to the reaction at 0° C. to a reflux temperature under heatingfor generally 0.5 hours to 1 day. The reaction is preferably performedunder an inert gas atmosphere such as nitrogen. Here, the solventincludes, though not particularly limited, for example: aromatichydrocarbons such as benzene, toluene and xylene; ethers such as diethylether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and1,2-diethoxy ethane; halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane and chloroform; N,N-dimethylformamide (DMF);N-methylpyrrolidone; dimethyl sulfoxide (DMSO); acetic acid; propionicacid; or a mixed solvent thereof.

Synthesis of Compound (B-10)

(wherein R₄ represents a protective group of a carboxyl group and R₆represents a methyl group or a p-tolyl group.) The synthesis method is amethod for synthesizing a 1,2,3-triazole ring by reacting the compound(B-6) and the compound (B-9). The reaction is performed by reacting thecompound (B-6) and the compound (B-9) in an equivalent amount or usingan excessive amount of one of the compounds in the presence of a base ina solvent inactive to the reaction at room temperature to a refluxtemperature under heating for generally 0.5 hours to 2 days. Thereaction is preferably performed under an inert gas atmosphere such asnitrogen. Examples of the base to be used include a carbonate such aspotassium carbonate, sodium carbonate and sodium hydrogen carbonate oran organic amine such as triethylamine, pyridine, 4-aminopyridine,N-ethyl-N,N-diisopropylamine (DIPEA) and1,8-diazabicyclo[5.4.0]-7-undecene (DBU). Examples of the solvent to beused for these reactions include toluene, benzene, pyridine, ethylacetate, dichloromethane, dichloroethane, chloroform, carbontetrachloride, diethyl ether, tetrahydrofuran (THF), 1,4-dioxane,1,2-dimethoxy ethane, 1,2-diethoxy ethane, N,N-dimethylformamide (DMF),N-methylpyrrolidone, dimethyl sulfoxide (DMSO) or a mixed solventthereof.

Synthesis of Compound (B-11)

(wherein R₄ represents a protective group of a carboxyl group.) Thesynthesis method is a method for synthesizing a compound (B-11) of thepresent invention by deprotecting a protective group R₄ of the compound(B-10) with an acid, a base or the like. The reaction is performed byreacting the compound (B-10) with an equivalent or excessive amount ofan acid or a base in a solvent inactive to the reaction at roomtemperature to a reflux temperature under heating for generally 0.5hours to 5 days. Here, the solvent includes, though not particularlylimited, for example: aromatic hydrocarbons such as benzene, toluene andxylene; ethers such as diethyl ether, tetrahydrofuran (THF),1,4-dioxane, 1,2-dimethoxy ethane and 1,2-diethoxy ethane; halogenatedhydrocarbons such as dichloromethane, 1,2-dichloroethane and chloroform;alcohols such as methanol, ethanol, 2-propanol and butanol;N,N-dimethylformamide (DMF); N-methylpyrrolidone; dimethyl sulfoxide(DMSO); water; or a mixed solvent thereof. Examples of the acid includean inorganic acid such as hydrogen chloride, hydrogen bromide, sulfuricacid, nitric acid and phosphoric acid or a solution obtained by dilutingthese acids with water or an organic solvent. Examples of the baseinclude an inorganic salt such as sodium hydroxide, potassium hydroxide,lithium hydroxide, sodium carbonate and potassium carbonate, a metalalkoxide such as sodium ethoxide and sodium methoxide or a solutionobtained by diluting these bases with water or an organic solvent.

Synthesis Method (C)

Synthesis of Compound (C-1)

(wherein R₄ represents a protective group of a carboxyl group and R₇represents an alkyl group such as a methyl group or an ethyl group.) Thesynthesis method is a method for synthesizing a tetrazole ring byreacting the compound (B-6) with an ortho-formic acid ester and an azidecompound. The reaction is performed by reacting the compound (B-6), anortho-formic acid ester and an azide compound in an equivalent amount orusing an excessive amount of one of the compounds in the presence of anacid in a solvent inactive to the reaction at room temperature to areflux temperature under heating for generally 0.5 hours to 2 days. Thereaction is preferably performed under an inert gas atmosphere such asnitrogen. Examples of the ortho-formic acid ester include trimethylortho-formate and triethyl ortho-formate. In addition, examples of theazide compound include sodium azide and trimethyl silylazide. Examplesof the acid to be used include an organic acid such as formic acid andacetic acid, an inorganic acid such as hydrochloric acid and sulfuricacid or a Lewis acid such as indium triflate, ytterbium triflate, zinctriflate and trichloroindium. The solvent to be used for these reactionsincludes, though not particularly limited, for example benzene, toluene,dichloromethane, dichloroethane, chloroform, carbon tetrachloride,diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane,1,2-diethoxy ethane, N,N-dimethylformamide (DMF), N-methylpyrrolidone,dimethyl sulfoxide (DMSO) or a mixed solvent thereof, and an acid suchas acetic acid may also be used as a solvent.

Synthesis of Compound (C-2)

(wherein R₄ represents a protective group of a carboxyl group.) Thesynthesis method is a method for synthesizing a compound (C-2) of thepresent invention by deprotecting a protective group R₄ of the compound(C-1) with an acid, a base or the like. The reaction is performed byreacting the compound (C-1) with an equivalent or excessive amount of anacid or a base in a solvent inactive to the reaction at room temperatureto a reflux temperature under heating for generally 0.5 hours to 5 days.Here, the solvent includes, though not particularly limited, forexample: aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane,1,2-dimethoxy ethane and 1,2-diethoxy ethane; halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane and chloroform; alcoholssuch as methanol, ethanol, 2-propanol and butanol; N,N-dimethylformamide(DMF); N-methylpyrrolidone; dimethyl sulfoxide (DMS 0); water; or amixed solvent thereof. Examples of the acid include an inorganic acidsuch as hydrogen chloride, hydrogen bromide, sulfuric acid, nitric acidand phosphoric acid or a solution obtained by diluting these acids withwater or an organic solvent. Examples of the base include an inorganicsalt such as sodium hydroxide, potassium hydroxide, lithium hydroxide,sodium carbonate and potassium carbonate, a metal alkoxide such assodium ethoxide and sodium methoxide or a solution obtained by dilutingthese bases with water or an organic solvent.

Synthesis of Compound (C-4)

(wherein R₄ represents a protective group of a carboxyl group and R₅represents a protective group of a phenolic hydroxyl group.) Thesynthesis method is a method for synthesizing a compound (C-4) bydeprotecting a protective group R₅ of the compound (C-3) with an acid, abase or the like. The reaction is performed by reacting the compound(C-3) with an equivalent or excessive amount of an acid or a base in asolvent inactive to the reaction at room temperature to a refluxtemperature under heating for generally 0.5 hours to 5 days. Here, thesolvent includes, though not particularly limited, for example: aromatichydrocarbons such as benzene, toluene and xylene; ethers such as diethylether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and1,2-diethoxy ethane; halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane and chloroform; alcohols such as methanol, ethanol,2-propanol and butanol; N,N-dimethylformamide (DMF);N-methylpyrrolidone; dimethyl sulfoxide (DMSO); water; or a mixedsolvent thereof. Examples of the acid include an inorganic acid such ashydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid andphosphoric acid or a solution obtained by diluting these acids withwater or an organic solvent. Examples of the base include an inorganicsalt such as sodium hydroxide, potassium hydroxide, lithium hydroxide,sodium carbonate, potassium carbonate, sodium ethocide and sodiummethoxide or a solution obtained by diluting these bases with water oran organic solvent.

In addition, the compound (C-1) may be synthesized, for example,according to the synthesis method described below.

Synthesis of Compound (C-1)

(wherein R₄ represents a protective group of a carboxyl group.) Thesynthesis method is a method for synthesizing the compound (C-1) byreacting the compound (C-4) with alcohols by Mitsunobu reaction or thelike. The reaction is a method for synthesizing the compound (C-1) byreacting alcohols with triphenylphosphine and carbodiimide, followed byreacting with the compound (C-4). Examples of the carbodiimide to beused include diethylcarbodiimide and diisopropylcarbodiimide. Thereaction is performed by reacting the compound (C-4) with an equivalentor excessive amount of alcohols, triphenylphosphine and carbodiimide ina solvent inactive to the reaction at −20° C. to 120° C. generally for0.5 to 12 hours. The reaction is preferably performed under an inert gasatmosphere such as nitrogen. Here, the solvent includes, though notparticularly limited, for example: aromatic hydrocarbons such asbenzene, toluene and xylene; ethers such as diethyl ether,tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and1,2-diethoxy ethane; N,N-dimethylformamide (DMF); N-methylpyrrolidone;dimethyl sulfoxide (DMSO); or a mixed solvent thereof.

Synthesis of Compound (D-1)

(wherein R₄ represents a protective group of a carboxyl group and Y₃ andY₅ represent a leaving group.) Examples of a leaving group representedby Y₃ and Y₅ include a halogen atom, a methanesulfonyloxy group, ap-toluenesulfonyloxy group and a trifluoromethanesulfonyloxy group. Thesynthesis method is a method for synthesizing a compound (D-1) bycoupling compounds (B-3) and (B-4). The reaction is performed byreacting the compounds (B-3) and (B-4) in an equivalent amount or usingan excessive amount of one of the compounds and adding a ligand,carboxylic acid and a monovalent or divalent copper salt in some cases,in the presence of a base and a transition metal catalyst in a solventinactive to the reaction at room temperature to a reflux temperatureunder heating for generally 0.5 hours to 2 days. The reaction ispreferably performed under an inert gas atmosphere such as nitrogen.Here, the solvent includes, though not particularly limited, forexample: aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane,1,2-dimethoxy ethane and 1,2-diethoxy ethane; halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane and chloroform; alcoholssuch as methanol, ethanol, 2-propanol and butanol; N,N-dimethylformamide(DMF); N-methylpyrrolidone; dimethyl sulfoxide (DMS 0); water or a mixedsolvent thereof. Examples of the base include: lithium hydride, sodiumhydride, potassium hydride, sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, cesium carbonate, potassiumfluoride, cesium fluoride, tripotassium phosphate, sodium acetate andpotassium acetate; a metal salt of an alkoxide having 1 to 6 carbonatoms (lithium salt, sodium salt, potassium salt and magnesium salt); ametal salt of an alkyl anion having 1 to 6 carbon atoms (lithium salt,sodium salt, potassium salt and magnesium salt); tetra (alkyl having 1to 4 carbon atoms) ammonium salt (fluoride, chloride and bromide);diisopropylethylamine; tributylamine; N-methylmorpholine;diazabicycloundecene; diazabicyclooctane; or imidazole. Examples of thetransition metal catalyst include copper, palladium, cobalt, iron,rhodium, ruthenium and iridium. Examples of the ligand includetri(t-butyl)phosphine, tri(cyclohexyl)phosphine,t-butyldicyclohexylphosphine, di(t-butyl)cyclohexylphosphine ordi(t-butyl)methylphosphine. Examples of the monovalent or divalentcopper salt include copper chloride (I), copper bromide (I), copperiodide (I), copper acetate (I), copper fluoride (II), copper chloride(II), copper bromide (II), copper iodide (II), copper acetate (II), ahydrate thereof or a mixture thereof. Examples of the carboxylic acidinclude formic acid, acetic acid, propionic acid, n-butyric acid,isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid andtrifluoroacetic acid.

Synthesis of Compound (D-2)

(wherein R₄ represents a protective group of a carboxyl group and Y₃represents a leaving group.) Examples of a leaving group represented byY₃ include a halogen atom, a methanesulfonyloxy group, ap-toluenesulfonyloxy group and a trifluoromethanesulfonyloxy group. Thereaction is a method for synthesizing a compound (D-2) by convertingthiols to corresponding lithium derivative, sodium derivative, potassiumderivative or cesium derivative with a base, followed by the reactionwith the compound (D-1). Examples of the base to be used include aninorganic salt such as sodium hydride, sodium hydroxide, potassiumhydroxide, lithium hydroxide, sodium carbonate, potassium carbonate andcesium carbonate, a metal alkoxide such as sodium ethoxide, sodiummethoxide and potassium t-butoxide or an organic amine such astriethylamine, pyridine, 4-aminopyridine, N-ethyl-N,N-diisopropylamine(DIPEA) and 1,8-diazabicyclo[5.4.0]-7-undecene (DBU). The reaction isperformed by reacting the compound (D-1) with an equivalent or slightlyexcessive amount of a base in a solvent inactive to the reaction at −20°C. to 120° C., followed by adding an equivalent or excessive amount ofthiols to allow the reaction to proceed generally for 0.5 to 12 hours.The reaction is preferably performed under an inert gas atmosphere suchas nitrogen. Here, the solvent includes, though not particularlylimited, for example: aromatic hydrocarbons such as benzene, toluene andxylene; ethers such as diethyl ether, tetrahydrofuran (THF),1,4-dioxane, 1,2-dimethoxy ethane and 1,2-diethoxy ethane;N,N-dimethylformamide (DMF); N-methylpyrrolidone; dimethyl sulfoxide(DMSO); or a mixed solvent thereof.

Synthesis of Compound (D-3)

(wherein R₄ represents a protective group of a carboxyl group.) Thesynthesis method is a method for synthesizing a compound (D-3) by thereduction of a nitro group of the compound (D-2). The reaction isperformed by reacting the compound (D-2) in a hydrogen gas atmosphereunder the presence of a transition metal catalyst in a solvent inactiveto the reaction at room temperature to a reflux temperature underheating for generally 0.5 hours to 2 days. Here, the solvent includes,though not particularly limited, for example: aromatic hydrocarbons suchas benzene, toluene and xylene; ethers such as diethyl ether,tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and1,2-diethoxy ethane; halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane and chloroform; alcohols such as methanol, ethanol,2-propanol and butanol; ethyl acetate; N,N-dimethylformamide (DMF);N-methylpyrrolidone; dimethyl sulfoxide (DMSO); or a mixed solventthereof. Preferred examples of the transition metal catalyst includepalladium-carbon, palladium hydroxide, palladium black, platinum-carbon,Raney nickel and the like.

Synthesis of Compound (D-4)

(wherein R₄ represents a protective group of a carboxyl group and R₇represents an alkyl group such as a methyl group or an ethyl group.) Thesynthesis method is a method for synthesizing a tetrazole ring byreacting the compound (D-3) with an ortho-formic acid ester and an azidecompound. The reaction is performed by reacting the compound (D-3), anortho-formic acid ester and an azide compound in an equivalent amount orusing an excessive amount of one of the compounds in the presence of anacid in a solvent inactive to the reaction at room temperature to areflux temperature under heating for generally 0.5 hours to 2 days. Thereaction is preferably performed under an inert gas atmosphere such asnitrogen. Examples of the ortho-formic acid ester include trimethylortho-formate and triethyl ortho-formate. In addition, examples of theazide compound include sodium azide and trimethyl silylazide. Examplesof the acid to be used include an organic acid such as formic acid andan inorganic acid such as acetic acid, hydrochloric acid and sulfuricacid and a Lewis acid such as indium triflate, ytterbium triflate, zinctriflate and trichloroindium. The solvent includes, though notparticularly limited, for example benzene, toluene, dichloromethane,dichloroethane, chloroform, carbon tetrachloride, diethyl ether,tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane, 1,2-diethoxyethane, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethylsulfoxide (DMSO) or a mixed solvent thereof, and an acid such as aceticacid may also be used as a solvent.

Synthesis of Compound (D-5)

(wherein R₄ represents a protective group of a carboxyl group.) Thesynthesis method is a method for synthesizing a compound (D-5) of thepresent invention by deprotecting a protective group R₄ of the compound(D-4) with an acid, a base or the like. The reaction is performed byreacting the compound (D-4) with an equivalent or excessive amount of anacid or a base in a solvent inactive to the reaction at room temperatureto a reflux temperature under heating for generally 0.5 hours to 5 days.Here, the solvent includes, though not particularly limited, forexample: aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane,1,2-dimethoxy ethane and 1,2-diethoxy ethane; halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane and chloroform; alcoholssuch as methanol, ethanol, 2-propanol and butanol; N,N-dimethylformamide(DMF); N-methylpyrrolidone; dimethyl sulfoxide (DMSO); water; or a mixedsolvent thereof. Examples of the acid include an inorganic acid such ashydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid andphosphoric acid or a solution obtained by diluting these acids withwater or an organic solvent. Examples of the base include an inorganicsalt such as sodium hydroxide, potassium hydroxide, lithium hydroxide,sodium carbonate and potassium carbonate, a metal alkoxide such assodium ethoxide and sodium methoxide or a solution obtained by dilutingthese bases with water or an organic solvent.

Synthesis Method (E)

Synthesis of Compound (E-2)

(wherein Y₃ and Y₅ represent a leaving group.) Examples of the leavinggroup represented by Y₃ and Y₅ include a halogen atom, amethanesulfonyloxy group, a p-toluenesulfonyloxy group and atrifluoromethanesulfonyloxy group. The reaction is a method forsynthesizing a compound (E-2) by converting amines to correspondinglithium derivative, sodium derivative, potassium derivative or cesiumderivative with a base, followed by the reaction with the compound(B-3). Examples of the base to be used include an inorganic salt such assodium hydride, sodium hydroxide, potassium hydroxide, lithiumhydroxide, sodium carbonate, potassium carbonate and cesium carbonate, ametal alkoxide such as sodium ethoxide, sodium methoxide and potassiumt-butoxide and an organic amine such as triethylamine, pyridine,4-aminopyridine, N-ethyl-N,N-diisopropylamine (DIPEA) and1,8-diazabicyclo[5.4.0]-7-undecene (DBU). The reaction is performed byreacting amines (E-1) with an equivalent or slightly excessive amount ofa base in a solvent inactive to the reaction at −20° C. to 120° C.,followed by adding the compound (B-3) to allow the reaction to proceedgenerally for 0.5 to 12 hours. The reaction is preferably performedunder an inert gas atmosphere such as nitrogen. Here, the solventincludes, though not particularly limited, for example: aromatichydrocarbons such as benzene, toluene and xylene; ethers such as diethylether, tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and1,2-diethoxy ethane; N,N-dimethylformamide (DMF); N-methylpyrrolidone;dimethyl sulfoxide (DMSO); or a mixed solvent thereof.

Synthesis of Compound (E-3)

(wherein R₄ represents a protective group of a carboxyl group and Y₅represent a leaving group.) The synthesis method is a method forsynthesizing a compound (E-3) by coupling the compounds (E-2) and (B-4).Examples of the leaving group represented by Y₅ include a halogen atom,a methanesulfonyloxy group, a p-toluenesulfonyloxy group and atrifluoromethanesulfonyloxy group. The reaction is performed by reactingthe compounds (E-2) and (B-4) in an equivalent amount or using anexcessive amount of one of the compounds, and adding a ligand,carboxylic acid and a monovalent or divalent copper salt in some cases,in the presence of a base and a transition metal catalyst in a solventinactive to the reaction at room temperature to a reflux temperatureunder heating for generally 0.5 hours to 2 days. The reaction ispreferably performed under an inert gas atmosphere such as nitrogen.Here, the solvent includes, though not particularly limited, forexample: aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane,1,2-dimethoxy ethane and 1,2-diethoxy ethane; halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane and chloroform; alcoholssuch as methanol, ethanol, 2-propanol and butanol; N,N-dimethylformamide(DMF); N-methylpyrrolidone; dimethyl sulfoxide (DMSO); water or a mixedsolvent thereof. Examples of the base include: lithium hydride, sodiumhydride, potassium hydride, sodium hydroxide, potassium hydroxide,sodium carbonate, potassium carbonate, cesium carbonate, potassiumfluoride, cesium fluoride, tripotassium phosphate, sodium acetate andpotassium acetate; a metal salt of an alkoxide having 1 to 6 carbonatoms (lithium salt, sodium salt, potassium salt and magnesium salt); ametal salt of an alkyl anion having 1 to 6 carbon atoms (lithium salt,sodium salt, potassium salt and magnesium salt); tetra (alkyl having 1to 4 carbon atoms) ammonium salt (fluoride, chloride and bromide);diisopropylethylamine; tributylamine; N-methylmorpholine;diazabicycloundecene; diazabicyclooctane; or imidazole. Examples of thetransition metal catalyst include copper, palladium, cobalt, iron,rhodium, ruthenium and iridium. Examples of the ligand includetri(t-butyl)phosphine, tri(cyclohexyl)phosphine,t-butyldicyclohexylphosphine, di(t-butyl)cyclohexylphosphine ordi(t-butyl)methylphosphine. Examples of the monovalent or divalentcopper salt include copper chloride (I), copper bromide (I), copperiodide (I), copper acetate (I), copper fluoride (II), copper chloride(II), copper bromide (II), copper iodide (II), copper acetate (II), ahydrate thereof and a mixture thereof. Examples of the carboxylic acidinclude formic acid, acetic acid, propionic acid, n-butyric acid,isobutyric acid, pentanoic acid, isopentanoic acid, pivalic acid andtrifluoroacetic acid.

Synthesis of Compound (E-4)

(wherein R₄ represents a protective group of a carboxyl group.) Thesynthesis method is a method for synthesizing a compound (E-4) by thereduction of a nitro group of the compound (E-3). The reaction isperformed by reacting the compound (E-3) in a hydrogen gas atmosphereunder the presence of a transition metal catalyst in a solvent inactiveto the reaction at room temperature to a reflux temperature underheating for generally 0.5 hours to 2 days. Here, the solvent includes,though not particularly limited, for example: aromatic hydrocarbons suchas benzene, toluene and xylene; ethers such as diethyl ether,tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane and1,2-diethoxy ethane; halogenated hydrocarbons such as dichloromethane,1,2-dichloroethane and chloroform; alcohols such as methanol, ethanol,2-propanol and butanol; ethyl acetate; N,N-dimethylformamide (DMF);N-methylpyrrolidone; dimethyl sulfoxide (DMSO); or a mixed solventthereof. Preferred examples of the transition metal catalyst includepalladium-carbon, palladium hydroxide, palladium black, platinum-carbonand Raney nickel.

Synthesis of Compound (E-5)

(wherein R₄ represents a protective group of a carboxyl group and R₇represents an alkyl group such as a methyl group or an ethyl group.) Thesynthesis method is a method for synthesizing a terazole ring byreacting the compound (E-4) with an ortho-formic acid ester and an azidecompound. The reaction is performed by reacting the compound (E-4), anortho-formic acid ester and an azide compound in an equivalent amount orusing an excessive amount of one of the compounds in the presence of anacid in a solvent inactive to the reaction at room temperature to areflux temperature under heating for generally 0.5 hours to 2 days. Thereaction is preferably performed under an inert gas atmosphere such asnitrogen. Examples of the ortho-formic acid ester include trimethylortho-formate and triethyl ortho-formate. In addition, examples of theazide compound include sodium azide and trimethyl silylazide. Examplesof the acid to be used include an organic acid such as formic acid andacetic acid; an inorganic acid such as hydrochloric acid and sulfuricacid or a Lewis acid such as indium triflate, ytterbium triflate, zinctriflate and trichloroindium. Examples of the solvent to be used forthese reaction include toluene, benzene, dichloromethane,dichloroethane, chloroform, carbon tetrachloride, diethyl ether,tetrahydrofuran (THF), 1,4-dioxane, 1,2-dimethoxy ethane, 1,2-diethoxyethane, N,N-dimethylformamide (DMF), N-methylpyrrolidone, dimethylsulfoxide (DMSO) or a mixed solvent thereof, and an acid such as aceticacid may also be used as a solvent.

Synthesis of Compound (E-6)

(wherein R₄ represents a protective group of a carboxyl group.) Thesynthesis method is a method for synthesizing a compound (E-6) of thepresent invention by deprotecting a protective group R₄ of the compound(E-5) with an acid, a base or the like. The reaction is performed byreacting the compound (E-5) with an equivalent or excessive amount of anacid or a base in a solvent inactive to the reaction at room temperatureto a reflux temperature under heating for generally 0.5 hours to 5 days.Here, the solvent includes, though not particularly limited, forexample: aromatic hydrocarbons such as benzene, toluene and xylene;ethers such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane,1,2-dimethoxy ethane and 1,2-diethoxy ethane; halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane and chloroform; alcoholssuch as methanol, ethanol, 2-propanol and butanol; N,N-dimethylformamide(DMF); N-methylpyrrolidone; dimethyl sulfoxide (DMSO); water; or a mixedsolvent thereof. Examples of the acid include an inorganic acid such ashydrogen chloride, hydrogen bromide, sulfuric acid, nitric acid andphosphoric acid or a solution obtained by diluting these acids withwater or an organic solvent. Examples of the base include an inorganicsalt such as sodium hydroxide, potassium hydroxide, lithium hydroxide,sodium carbonate, potassium carbonate, a metal alkoxide such as sodiumethoxide and sodium methoxide or a solution obtained by diluting thesebases with water and the like.n the above synthesis methods, the compounds of the formulas (A-8),(B-10), (C-1), (C-4), (D-4) and (E-5) correspond to the compound of theformula (II), which is a manufacturing intermediate of the compoundrepresented by the formula (I), and the compound of the formula (C-3)corresponds to the compound of the formula (III).

Hereinafter, among the compounds represented by the formula (I),preferred compounds and pharmaceutically acceptable salts thereofinclude though not particularly limited, for example, a salt with aninorganic acid such as hydrochloric acid, hydrogen bromide, sulfuricacid, nitric acid, phosphoric acid and carbonic acid; a salt with anorganic acid such as maleic acid, fumaric acid, citric acid, malic acid,tartaric acid, lactic acid, succinic acid, benzoic acid, oxalic acid,methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,acetic acid, trifluoroacetic acid and formic acid; a salt with an aminoacid such as glycine, lysine, arginine, histidine, ornithine, glutamicacid and aspartic acid; a salt with an alkali metal such as sodium,potassium and lithium; a salt with an alkali earth metal such as calciumand magnesium; a salt with metal such as aluminum, zinc and iron; a saltwith an organic onium such as tetramethylammonium and choline; or a saltwith an organic base such as ammonia, propanediamine, pyrrolidine,piperidine, pyridine, ethanolamine, N,N-dimethylethanolamine,4-hydroxypiperidine, t-octylamine, dibenzylamine, morpholine,glucosamine, phenylglycylalkyl ester, ethylenediamine,N-methylglucamine, guanidine, diethylamine, triethylamine,dicyclohexylamine, N,N′-dibenzylethylenediamine, chloroprocaine,procaine, diethanolamine, N-benzylphenylamine, piperazine, andtris(hydroxymethyl)aminomethane.

Further, examples of the compound represented by the formula (I) and asalt thereof include various hydrates and solvates. The solvent of thesolvates includes, though not particularly limited, for examplemethanol, ethanol, 1-propanol, 2-propanol, butanol, t-butanol,acetonitrile, acetone, methyl ethyl ketone, chloroform, ethyl acetate,diethyl ether, t-butylmethyl ether, tetrahydrofuran (THF), 1,4-dioxane,1,2-dimethoxy ethane, 1,2-diethoxy ethane, benzene, toluene, DMF andDMSO.

The above various pharmaceutically acceptable salts of the compoundrepresented by the formula (I) may be appropriately manufactured basedon conventional knowledge in the art.

Examples of the compound of the present invention include stereoisomers,recemates and all possible optically active substances of the compoundrepresented by the formula (1) and a salt thereof.

A compound represented by the formula (I) and a pharmaceuticallyacceptable salt thereof have especially excellent xanthine oxidaseinhibitory activity. Because of the excellent xanthine oxidaseinhibitory activity, the compound represented by the formula (I) and thepharmaceutically acceptable salt thereof are useful as a xanthineoxidase inhibitor.

A compound represented by the formula (I) of the present invention and apharmaceutically acceptable salt thereof may be used as a therapeuticagent or a preventive agent which can be clinically applied as axanthine oxidase inhibitor for diseases associated with xanthine oxidasesuch as gout, hyperuricemia, tumor lysis syndrome, urinary calculi,hypertension, dyslipidemia, diabetes, kidney diseases such as diabeticnephropathy, respiratory diseases such as chronic obstructive pulmonarydiseases, inflammatory bowel diseases or autoimmune diseases.

In the present invention, the term “prophylactic” means to prevent theincidence or onset of diseases in an individual who is not affected bydiseases or has not yet developed diseases and the term “therapeutic”means to treat, suppress or remedy diseases or symptoms in an individualwho has already been affected by diseases or has developed diseases.

In the present invention, a vascular endothelial function is a functionto regulate shrinkage and relaxation of vessel walls caused by variousvasoactive substance released by vascular endothelium, adhesion ofinflammatory cells to vessel walls, blood vessel permeability andcongealing fibrinogenolysis system, and a vascular endothelial functiondisorder is a state in which these regulations do not function normallydue to a disorder caused by some kind of reason.

A compound of the present invention represented by the formula (I) and apharmaceutically acceptable salt thereof are useful as a drug forimproving vascular endothelial function through the inhibition ofreactive oxygen species production by the xanthine oxidase inhibition inblood vessel. Here, the vascular endothelial function improvement refersto bringing a vascular endothelial function close to a normal state.

The compound represented by the above-mentioned formula (1) and thepharmaceutically acceptable salt thereof can be used to prepare apharmaceutical composition together with a pharmaceutically acceptablecarrier and/or excipient. The pharmaceutical composition can be formedinto various formulations for oral or parenteral administration.Examples of a parenteral administration include intravenous,subcutaneous, intramuscular, percutaneous or intrarectal administration.

A drug formulation containing one or more of the compounds representedby formula (1) of the present invention or the pharmaceuticallyacceptable salt thereof as an active ingredient is prepared using acarrier, an excipient or other additives which are usually used for drugformulation. Any of solid and liquid forms may be used as a carrier oran excipient for pharmaceutical preparations, and examples of whichinclude lactose, magnesium stearate, starch, talc, gelatin, agar,pectin, gum arabic, olive oil, sesame oil, cacao butter, ethyleneglycol,and others in common use. Administration may be done in any form of oraladministration with tablets, pills, capsules, granules, powders, liquidsor the like, parenteral administration by injections for intravenous orintramuscular injection, suppository, percutaneous administration or thelike.

A compound represented by the formula (1) of the present invention or apharmaceutically acceptable salt thereof can be administered usually inthe range of 0.01 to 1,000 mg once or several times a day for adult.However, the dosage varies depending on the kind of disease,administration route, or symptom, age, sex or body weight of thepatient, and the like. However, since the dosage varies according tovarious conditions, a dosage smaller than the above-mentioned dosage maybe sufficient in some cases and a dosage exceeding the above range maybe necessary in other cases.

EXAMPLES

Hereinafter, the present invention will be explained based on specificexamples. However, the present invention is not limited to theseexamples.

The structure of the novel compound isolated was confirmed by ¹H-NMRand/or mass spectrometry using single quadrupole instrumentationequipped with an electron spray source and other appropriate analyticalmethods.

As for the compounds for which ¹H-NMR spectrum (300 MHz or 400 MHz,DMSO-d₆ or CDCl₃) was measured, the chemical shift (δ: ppm) and couplingconstant (J: Hz) are shown. As for the result of mass spectroscopy, theobserved value of M⁺+H, that is, the observed value is shown as thevalue of the molecular mass of the compound (M) with a proton (H⁺). Inaddition, the following abbreviations represent the followings,respectively: s=singlet, d=doublet, t=triplet, q=quartet, brs=broadsinglet, m=multiplet.

The compounds synthesized according to the following methods of exampleswere further analyzed by high performance liquid chromatography (HPLC)analysis and mass spectrometry using Time-of-Flight mass spectrometerequipped with an electron spray source.

The retention time (unit: min.) of compounds in the HPLC analysis underthe following analytical conditions is shown as HPLC retention time.

HPLC Measurement Conditions

-   Measurement Device: Hewlett-Packard 1100HPLC-   Column: Imtakt Cadenza CD-C18 100 mm×4.6 mm 3 μm-   UV: PDA detection (254 nm)-   Column Temperature: 40° C.-   Gradient Conditions:-   Solvent: A: H₂O/acetonitrile=95/5    -   0.05% TFA (trifluoroacetic acid)    -   B: H₂O/acetonitrile=5/95    -   0.05% TFA (trifluoroacetic acid)-   Flow Rate: 1.0 mL/min-   Gradient: 0 to 1 min, Solvent B: 2%, Solvent A: 98% 1 to 14 min,    Solvent B: 2% to 100%, Solvent A: 98% to 0% 14 to 17 min, Solvent B:    100%, Solvent A: 0% 17 to 19 min, Solvent B: 100% to 2%, Solvent A:    0% to 98%

In addition, for the result of the mass analysis, the value of “M⁺+H”(Obs. Mass: that is, the observed value in which a proton is added tothe molecular mass (M) of the compound), which was observed by thefollowing devices and analytical conditions, and the formulas calculatedfrom the value of “M⁺+H” observed are shown together with the calculatedvalues of “M⁺+H” (Pred. Mass).

TOF-MS Measurement Conditions

-   Mass Spectrometer: Shimadzu LCMS-IT-TOF-   LC: Prominence-   Column: Phenomenex×Synergi Hydro-RP 4.0 mm×20 mm 2.5 μm-   UV: PDA detection (254 nm)-   Flow Rate: 0.6 mL/min-   Column Temperature: 40° C.-   Detection Voltage: 1.63 kV-   Gradient Conditions:-   Solvent: A: H₂O/acetonitrile=95/5    -   0.1% HCOOH    -   B: H₂O/acetonitrile=5/95    -   0.1% HCOOH-   Flow Rate: 0.5 mL/min-   Gradient: 0 to 0.2 min, Solvent B: 2%, Solvent A: 98% 0.2 to 2.5    min, Solvent B: 2% to 100%, Solvent A: 98% to 0% 2.5 to 3.8 min,    Solvent B: 100%, Solvent A: 0% 3.8 to 4.0 min, Solvent B: 100% to    2%, Solvent A: 0% to 98% 4.0 to 5.0 min, Solvent B: 2%, Solvent A:    98%

Reference Example Synthesis ofN′-[(1E)-2,2-dichloroethylidene]-4-methylbenzene-1-sulfonehydrazine(reference example compound)

A reaction solution was prepared by dissolving 1.86 g ofp-toluenesulfonylhydrazine in 4 mL of propionic acid and cooling at 0°C. and adding dropwise slowly a solution prepared by dissolving 1.36 gof dichloroacetaldehyde hydrate in 8 mL of propionic acid. The reactionsolution was stirred at 0° C. for one hour and the precipitated solidwas filtered, washed using 10 mL of toluene and dried to obtain 1.98 gof N′-[(1E)-2,2-dichloroethylidene]-4-methylbenzene-1-sulfonehydrazine.

¹H-NMR (400 MHz, CDCl₃)δ(ppm): 2.45 (3H,$), 6.11 (1H, d, J=8.0 Hz), 7.19(1H, d, J=4.0 Hz), 7.35 (1H, d, J=8.0 Hz), 7.80 (1H, d, J=8.0 Hz), 7.92(1H, s)

Example 1 Synthesis of2-[3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylicacid (Compound No. 1) (Synthesis Method (A))

(1) A reaction mixture solution prepared by suspending 41.1 mg of3-fluoro-4-hydroxybenzonitrile, 33.4 mg of isobutyl bromide and 62.2 mgof potassium carbonate in 1 mL of dimethylformamide was heated at 110°C. for 5 hours under a nitrogen atmosphere. After the addition of waterto the reaction mixture solution, extraction was performed using ethylacetate. The organic layer was washed with saline, followed by dryingand concentrating under reduced pressure to obtain a crude product of3-fluoro-4-(2-methylpropoxy) benzonitrile.(2) A reaction mixture prepared by adding 15.7 mg of sodium hydride and24.5 mg of imidazole to the crude product of3-fluoro-4-(2-methylpropoxy)benzonitrile obtained above and suspendingthe above in 1 mL of dimethylsulfoxide was heated at 110° C. for 5 hoursunder a nitrogen atmosphere. After the addition of water to the reactionmixture solution, extraction was performed using ethyl acetate. Theorganic layer was washed with saline, followed by drying andconcentrating under reduced pressure to obtain a crude product of3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzonitrile.

ESI/MS m/e: 242.1 (M⁺+H, C₁₄H₁₆N₃O).

(3) A reaction mixture prepared by suspending the crude product of3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzonitrile obtained above in amixture of 0.2 mL of acetic acid and 0.5 mL of thioacetic acid washeated at 50° C. for 14 hours under a nitrogen atmosphere. Concentrationunder reduced pressure was prepared to obtain a crude product of3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzene-1-carbothioamide.

ESI/MS m/e: 276.1 (M⁺+H, C₁₄H₁₈N₃OS).

(4) A reaction mixture solution prepared by adding 74.1 mg ofethyl-2-chloroacetacetate to the crude product of3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)benzene-1-carbothioamideobtained above and suspending the above mixture in 1 mL of ethanol washeated at 80° C. for 5 hours under a nitrogen atmosphere. After theaddition of water to the reaction mixture solution, extraction wasperformed using ethyl acetate. The organic layer was washed with saline,followed by drying and concentrating under reduced pressure to obtain acrude product of2-[3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 386.1 (M⁺+H, C₂₀H₂₄N₃O₃S).

(5) A reaction mixture solution prepared by dissolving the crude productof2-[3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylateobtained above in 1 mL of a mixed solution oftetrahydrofuran/methanol=1/1 followed by the addition of 0.2 mL of 2 Msodium hydroxide aqueous solution was stirred at room temperature for 4hours. After the addition of 0.2 mL of 2 M hydrochloric acid to thereaction mixture solution under stirring, 3 mL of water was added andextraction was performed using 4 mL of ethyl acetate. The organic phasewas concentrated, followed by purifying by a conventional method toobtain 2.50 mg of2-[3-(1H-imidazol-1-yl)-4-(2-methylpropoxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylicacid.

¹H-NMR (400 MHz, DMSO d6) δ(ppm): 0.89 (6H, d, J=6.4 Hz), 1.96-2.02 (1H,m), 2.65 (3H, s), 3.92 (2H, d, J=6.4 Hz), 7.13 (1H, s), 7.37 (1H, d,J=8.8 Hz), 7.55 (1H, s), 7.95-8.07 (3H, m)

-   HPLC Retention Time: 8.15 min.-   Obs Mass (M⁺+H): 358.1215-   Pred Mass (M⁺+H): 358.1220-   Formula (M): C₁₈H₁₉N₃O₃S

Examples 2 to 6

The compounds of Compound Nos. 2 to 6 were synthesized in the similarmanner as in Example 1.

Com- HPLC pound Retention Obs Mass Pred Mass Example No. Time (M+ + H)(M+ + H) Formula(M) 1H NMR 2 2 8.61 372.1380 372.1376 C19H21N3O3S 3 38.39 370.1234 370.1220 C19H19N3O3S 400 MHz (DMSO d6) 1.78-2.03(7H, m),2.64(3H, s), 4.10(2H, d, J = 6.4 Hz), 7.07(1H, s), 7.36(1H, d, J = 8.8Hz), 7.53(1H, s), 7.91-7.98(3H, m) 4 4 8.90 384.1376 384.1376C20H21N3O3S 400 MHz (DMSO d6) 1.25-1.73(9H, m), 2.64(3H, s), 4.02(2H, d,J = 6.8 Hz), 7.07(1H, s), 7.36(1H, d, J = 8.8 Hz), 7.52(1H, t, J = 1.6Hz), 7.92(1H, d, J = 2.0 Hz), 7.97-7.99(2H, m) 5 5 8.23 370.1214370.1220 C19H19N3O3S 6 6 8.71 384.1377 384.1376 C20H21N3O3S 400 MHz(DMSO d6) 1.25-1.57(8H, m), 1.84- 1.90(2H, m), 2.65(3H, s),4.57-4.61(1H, m), 7.07(1H, s), 7.40(1H, d, J = 8.8 Hz), 7.52(1H, s),7.92-7.99(3H, m)

[Example 7] Synthesis of2-[3-(1H-imidazol-1-yl)-4-phenoxyphenyl]-4-methyl-1,3-thiazole-5-carboxylicacid (Compound No. 7) (Synthesis Method (A))

(1) A reaction mixture solution prepared by suspending 77.8 mg of3-chloro-4-fluorobenzonitrile, 51.8 mg of phenol and 82.9 mg ofpotassium carbonate in 2 mL of dimethylsulfoxide was heated at 100° C.for 14 hours under a nitrogen atmosphere. Subsequently, 24.0 mg ofsodium hydroxide and 40.8 mg of imidazole were added to the reactionmixture solution, and the mixture was heated at 140° C. for 5 hoursunder a nitrogen atmosphere. After the addition of water to the reactionmixture solution, extraction was performed using ethyl acetate. Theorganic phase is washed with saline, followed by drying andconcentrating under reduced pressure. The resulting crude product wasseparated and purified by silica gel column chromatography to obtain65.2 mg of 3-(1H-imidazol-1-yl)-4-phenoxybenzonitrile.

ESI/MS m/e: 262.2 (M⁺+H, C₁₆H₁₂N₃O).

(2) A reaction mixture prepared by suspending 65.2 mg of3-(1H-imidazol-1-yl)-4-phenoxybenzonitrile in a mixture of 0.3 mL ofacetic acid and 1.0 mL of thioacetic acid was heated at 50° C. for 14hours under a nitrogen atmosphere. A crude product of3-(1H-imidazol-1-yl)-4-phenoxybenzene-1-carbothioamide was obtained byconcentrating under reduced pressure.

ESI/MS m/e: 296.1 (M⁺+H, C₁₆H₁₄N₃OS).

(3) A reaction mixture solution prepared by adding 123.2 mg ofethyl-2-chlioroacetacetate to the crude product of3-(1H-imidazol-1-yl)-4-phenoxybenzene-1-carbothioamide obtained aboveand suspending the mixture in 2 mL of ethanol was heated at 80° C. for 5hours under a nitrogen atmosphere. After the addition of water to thereaction mixture solution, extraction was performed using ethyl acetate.The organic layer was washed with saline, followed by drying andconcentrating under reduced pressure. The resulting crude product wasseparated and purified by silica gel column chromatography to obtain72.2 mg of2-[3-(1H-imidazol-1-yl)-4-phenoxyphenyl]-4-methyl-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 406.1 (M⁺+H, C₂₂H₂₀N₃O₃S).

(4) A reaction mixture solution was prepared by dissolving 20.2 mg of2-[3-(1H-imidazol-1-yl)-4-phenoxyphenyl]-4-methyl-1,3-thiazole-5-carboxylateobtained above in 1 mL of a mixed solution oftetrahydrofuran/methanol=1/1 and adding 0.2 mL of 2 M sodium hydroxideaqueous solution. The reaction mixture was stirred at 50° C. for 2hours. After the addition of 0.2 mL of 2 M hydrochloric acid to thereaction mixture solution under stirring, 3 mL of water was added andextraction was performed using 4 mL of ethyl acetate. The organic phasewas concentrated, followed by purifying using a conventional method toobtain 9.0 mg of2-[3-(1H-imidazol-1-yl)-4-phenoxyphenyl]-4-methyl-1,3-thiazole-5-carboxylicacid.

¹H-NMR (400 MHz, DMSO d6) δ(ppm): 2.61 (3H, s), 7.07-7.13 (3H, m), 7.20(1H, t, J=6.8 Hz), 7.42 (2H, t, J=8.0 Hz), 7.59 (2H, s), 7.74 (1H, d,J=7.6 Hz), 7.86 (1H, dd, J=1.2, 8.4 Hz), 8.08 (1H, s)

-   HPLC Retention Time: 7.86 min.-   Obs Mass (M⁺+H): 378.0906-   Pred Mass (M⁺+H): 378.0907-   Formula (M): C₂₀H₁₅N₃O₃S

Example 8

The compound of Compound No. 8 was synthesized in the similar manner asin Example 7.

HPLC Compound Retention Obs Mass Pred Mass Example No. Time (M+ + H)(M+ + H) Formula(M) 1H NMR 8 8 7.81 396.0815 396.0813 C20H14FN3O3S 400MHz (DMSO d6) 2.60(3H, s), 7.10(1H, s), 7.24-7.47(4H, m), 7.50(1H, d, J= 1.2 Hz), 7.61 (1H, s), 7.75(1H, t, J = 8.4 Hz), 7.85(1H, dd, J = 1.2,8.0 Hz), 8.09(1H, s)

Examples 9 to 14

The compounds of Compound Nos. 9 to 14 were synthesized in the similarmanner as in Example 1.

Com- HPLC Ex- pound Retention Obs Mass Pred Mass ample No. Time (M+ + H)(M+ + H) Formula(M) 1H NMR 9 9 8.36 372.1380 372.1376 C19H21N3O3S 400MHz (DMSO d6) 0.83(6H, d, J = 6.8 Hz), 1.86- 1.94(1H, m), 2.41(3H, s),2.65(3H, s), 3.93(2H, d, J = 6.4 Hz), 7.46(1H, d, J = 8.8 Hz), 7.77(1H,d, J = 2.0 Hz), 7.82(1H, d, J = 2.0 Hz), 8.18-8.22(2H, m) 10 10 11.10374.1272 374.1281 C17H19N5O3S 400 MHz (DMSO d6) 0.98(6H, d, J = 6.8 Hz),2.01- 2.08(1H, m), 2.39(3H, s), 2.50(3H, s), 3.90(2H, d, J = 6.8 Hz),7.24(1H, t, J = 8.4 Hz), 7.64(1H, dd, J = 2.0, 7.6 Hz), 7.72(1H, d, J =8.4 Hz) 11 11 9.49 408.1388 408.1376 C22H21N3O3S 400 MHz (DMSO d6)0.72(6H, d, J = 6.8 Hz), 1.45- 1.83(1H, m), 2.65(3H, s), 3.89(2H, d, J =6.4 Hz), 7.25-7.29(3H, m), 7.44(1H, d, J = 8.8 Hz), 7.74- 7.76(1H, m),8.08-8.13(2H, m), 8.40(1H, s), 13.35(1H, s) 12 12 10.85 373.1341373.1329 C18H20N4O3S 400 MHz (DMSO d6) 0.95(6H, d, J = 6.4 Hz), 2.04-2.11(1H, m), 2.37(3H, s), 2.65(3H, s), 3.98(2H, d, J = 6.4 Hz), 7.38(1H,d, J = 8.8 Hz), 7.94(1H, dd, J = 2.4, 8.8 Hz), 8.24(1H, d, J = 2.4 Hz),8.81(1H, s) 13 13 10.71 359.1165 359.1172 C17H18N4O3S 400 MHz (DMSO d6)0.93(6H, d, J = 6.8 Hz), 2.01- 2.11(1H, m), 2.65(3H, s) 3.98(2H, d, J =6.8 Hz), 7.41(1H, d, J = 8.8 Hz), 8.00(1H, dd, J = 2.4, 8.8 Hz),8.23-8.25(2H, m), 8.95(1H, s) 14 14 9.82 373.1335 373.1329 C18H20N4O3S400 MHz (DMSO d6) 0.81(6H, d, J = 6.4 Hz), 1.85- 1.90(1H, m), 2.25(3H,s), 2.65(3H, s), 3.89(2H, d, J = 6.4 Hz), 7.39(1H, d, J = 8.8 Hz),7.98-8.02(2H, m), 8.11-8.13(1H, m)

Example 15

The compound of Compound No. 15 was synthesized in the similar manner asin Example 7.

Com- HPLC Pred Ex- pound Retention Obs Mass Mass ample No. Time (M+ + H)(M+ + H) Formula(M) 1H NMR 15 15 10.51 379.0871 379.0859 C19H14N4O3S 400MHz (DMSO d6) 2.61(3H, s), 7.16-7.25(3H, m), 7.44(2H, t, J = 7.6 Hz),7.60(1H, s), 7.92(2H, dd, J = 8.4 Hz), 8.24(1H, s), 9.09(1H, s)

Example 16 Synthesis of4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylicacid (Compound No. 16) (Synthesis Method (B))

(1) A reaction mixture solution prepared by suspending 2.18 g of4-bromo-2-nitrophenol and 2.07 g of potassium carbonate in 40 mL ofdimethylformamide and adding 2.04 g of isopropyl iodide was heated understirring at 110° C. for 14 hours under a nitrogen atmosphere. After theaddition of water to the reaction mixture solution, extraction wasperformed using ethyl acetate. The organic layer was washed with saline,followed by drying and concentrating under reduced pressure. Theresulting crude product was separated and purified by silica gel columnchromatography to obtain 2.08 g of4-bromo-2-nitro-1-(propan-2-yloxy)benzene.(2) A suspension was prepared by adding 1.05 g of potassium hydrogencarbonate, 22 mg of palladium chloride (II) and 102 mg of a copperbromide (I) dimethylsulfide complex to 2.08 g of4-bromo-2-nitro-1-(propan-2-yloxy)benzene obtained above, followed bysuspending the mixture in 15 mL of toluene. Subsequently, a reactionmixture solution prepared by adding 1.02 g of ethyl4-methyl-1,3-thiazole-5-carboxylate, 46.2 μL of isobutyric acid and 114mg of di-t-butylcyclohexylphosphine to the suspension was heated at 120°C. for 14 hours under a nitrogen atmosphere. The reaction mixturesolution was celite-filtered to remove insoluble matter, water was addedto the filtrate, extraction was performed using ethyl acetate. Theorganic layer was washed with saline and then dried and concentratedunder reduced pressure, followed by purifying by a conventional methodto obtain 1.38 g of ethyl4-methyl-2-[3-nitro-4-(propan-2-yloxy)phenyl]-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 351.0 (M⁺+H, C₁₆H₁₉N₂O₅S).

(3) A reaction mixture solution prepared by suspending 1.38 g of ethyl4-methyl-2-[3-nitro-4-(propan-2-yloxy)phenyl]-1,3-thiazole-5-carboxylatein 15 mL of ethanol and adding 100 mg of palladium/carbon (10 wt %) tothe suspension was heated under stirring at 50° C. for 14 hours under ahydrogen atmosphere. The reaction mixture solution was celite-filteredand the filtrate was concentrated under reduced pressure to obtain 1.26g of ethyl2-[3-amino-4-(propan-2-yloxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 321.1 (M⁺+H, C₁₆H₂₁N₂O₃S).

(4) A reaction solution prepared by suspending 1.26 g of ethyl2-[3-amino-4-(propan-2-yloxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylatein 10 mL of methanol and adding 1.12 mL of triethylamine to thesuspension was cooled to 0° C. Subsequently, a reaction mixture solutionwas prepared by slowly adding a solution prepared by dissolving 1.01 gof N′-[(1E)-2,2-dichloroethylidene]-4-methylbenzene-1-sulfonehydrazinein 10 mL of methanol to the reaction solution, and the mixture washeated at 40° C. for 2 hours under a nitrogen atmosphere. After theaddition of water to the reaction mixture solution, extraction wasperformed using ethyl acetate. The organic layer was washed with saline,followed by drying and concentrating under reduced pressure. Theresulting crude product was separated and purified by silica gel columnchromatography to obtain 501 mg of ethyl4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 373.1 (M⁺+H, C₁₈H₂₁N₄O₃S)

(5) A reaction mixture solution prepared by dissolving 501 mg of ethyl4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylatein 10 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding1.35 mL of 2 M sodium hydroxide aqueous solution was stirred at roomtemperature for 3 hours. After the addition of 1.35 mL of 2 Mhydrochloric acid to the reaction mixture solution under stirring, 8 mLof water was added and extraction was performed using 20 mL of ethylacetate. The organic phase was concentrated, followed by purifying by aconventional method to obtain 415 mg of4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylicacid.

¹H-NMR (400 MHz, DMSO d6) δ(ppm): 1.28 (6H, d, J=5.6 Hz), 2.66 (3H, s),4.83-4.89 (1H, m), 7.46 (1H, d, J=8.8 Hz), 7.95 (1H, s), 8.06 (1H, dd,J=2.0, 8.8 Hz), 8.22 (1H, dd, J=2.8 Hz), 8.52 (1H, s), 13.39 (1H, s)

-   HPLC Retention Time: 9.96 min.-   Obs Mass (M⁺+H): 345.1005-   Pred Mass (M⁺+H): 345.1016-   Formula (M): C₁₆H₁₆N₄O₃S

Examples 17 to 21

The compounds of Compound Nos. 17 to 21 were synthesized in the similarmanner as in Example 16.

Com- HPLC Ex- pound Retention Obs Mass Pred Mass ample No. Time (M+ + H)(M+ + H) Formula(M) 1H NMR 17 17 10.91 359.1168 359.1172 C17H18N4O3S 400MHz (DMSO d6) 0.88(6H, d, J = 6.8 Hz), 1.95- 2.02(1H, m), 2.66(3H, s),3.95(2H, d, J = 6.4 Hz), 7.44(1H, d, J = 8.8 Hz), 7.97(1H, s), 8.10(1H,dd, J = 2.4, 8.8 Hz), 8.21(1H, d, J = 2.4 Hz), 8.51(1H, d, J = 0.8 Hz),13.40(1H, s) 18 18 11.44 373.1340 373.1329 C18H20N4O3S 400 MHz (DMSO d6)0.87(9H, m), 2.66(3H, s), 3.98(2H, s), 7.44(1H, d, J = 8.8 Hz), 7.98(1H,s), 8.11(1H, dd, J = 2.4, 8.8 Hz), 8.19(1H, d, J = 2.4 Hz), 8.49(1H, s),13.37(1H, brs) 19 19 11.29 371.1173 371.1172 C18H18N4O3S 400 MHz (DMSOd6) 1.78-1.99(7H, m), 2.66(3H, s), 4.15(2H, d, J = 6.4 Hz), 7.45(1H, d,J = 8.8 Hz), 7.96(1H, s), 8.10(1H, dd, J = 2.4, 8.8 Hz), 8.24(1H, d, J =2.0 Hz), 8.49(1H, s), 13.40(1H, brs) 20 20 9.29 331.0847 331.0859C15H14N4O3S 400 MHz (DMSO d6) 1.29(6H, d, J = 6.0 Hz), 4.83- 4.89(1H,m), 7.49(1H, d, J = 8.8 Hz), 7.95(1H, d, J = 0.8 Hz), 8.11(1H, dd, J =2.8, 8.8 Hz), 8.25(1H, d, J = 2.4 Hz), 8.39(1H, d, J = 2.0 Hz), 8.52(1H,d, J = 1.2 Hz), 13.58(1H, brs) 21 21 10.26 345.1011 345.1016 C16H16N4O3S400 MHz (DMSO d6) 0.88(6H, d, J = 6.8 Hz), 1.95- 2.02(1H, m), 3.96(2H,d, J = 6.0 Hz), 7.45(1H, d, J = 8.8 Hz), 7.96(1H, d, J = 0.8 Hz),8.14(1H, dd, J = 2.4, 8.8 Hz), 8.23(1H, d, J = 2.4 Hz), 8.39(1H, s),8.50 (1H, d, J = 0.8 Hz), 13.59(1H, brs)

Examples 22 and 23

The compounds of Compound Nos. 22 and 23 were synthesized in the similarmanner as in Example 7.

HPLC Compound Retention Obs Mass Pred Mass Example No. Time (M+ + H)(M+ + H) Formula(M) 1H NMR 22 22 10.68 379.0851 379.0859 C19H14N4O3S 400MHz (DMSO d6) 2.62(3H, s), 7.15(2H, d, J = 7.6 Hz), 7.21-7.25(1H, m),7.44(2H, t, J = 8.0 Hz), 7.62(1H, d, J = 0.8 Hz), 7.91-7.98(3H, m),8.64(1H, s), 13.50(1H, brs) 23 23 10.63 397.0777 397.0765 C19H13FN4O3S400 MHz (DMSO d6) 2.62(3H, s), 7.26-7.47(4H, m), 7.54(1H, s),7.91-7.98(3H, m), 8.64(1H, d, J = 0.8 Hz), 13.50(1H, brs)

Example 24 Synthesis of4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylicacid (Compound No. 24) (Synthesis Method (C))

(1) A suspension was prepared by suspending 1.23 g of ethyl2-[3-amino-4-(propan-2-yloxy)phenyl]-4-methyl-1,3-thiazole-5-carboxylatein 20 mL of acetic acid. A reaction mixture solution prepared by adding478 mg of sodium azide and 1.09 g of triethyl ortho formate to thesuspension was heated at 70° C. for 2 hours under a nitrogen atmosphere.After cooling the reaction mixture solution to room temperature, waterwas added to the reaction mixture solution, and extraction was performedusing ethyl acetate. The organic layer was washed with saline, dried andconcentrated under reduced pressure and purified by a conventionalmethod to obtain 1.13 g of ethyl4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 374.1 (M⁺+H, C₁₇H₂₀N₅O₃S)

(2) A reaction mixture solution prepared by dissolving 1.13 g of ethyl4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylatein 15 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding3.0 mL of 2 M sodium hydroxide aqueous solution to the mixture wasstirred at room temperature for 3 hours. After the addition of 3.0 mL of2 M hydrochloric acid to the reaction solution under stirring, 7 mL ofwater was added and extraction was performed using 30 mL of ethylacetate. The organic layer was concentrated, followed by purifying by aconventional method to obtain 920 mg of4-methyl-2-[4-(propan-2-yloxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylicacid.

¹H-NMR (400 MHz, DMSO d6) δ(ppm): 1.28 (6H, d, J=6.0 Hz), 2.65 (3H, s),4.84-4.90 (1H, m), 7.50 (1H, d, J=9.6 Hz), 8.13 (1H, dd, J=2.4, 8.8 Hz),8.27 (1H, d, J=2.4 Hz), 9.79 (1H, s), 13.41 (1H, s)

-   HPLC Retention Time: 9.99 min.-   Obs Mass (M⁺+H): 346.0958-   Pred Mass (M⁺+H): 346.0968-   Formula (M): C₁₅H₁₅N₆O₃S

Examples 25 to 30

The compounds of compound Nos. 25 to 28 were synthesized in the similarmanner as in Example 24.

Com- HPLC Obs Pred Ex- pound Retention Mass Mass ample No. Time (M+ + H)(M+ + H) Formula(M) 1H NMR 25 25 10.87 360.1124 360.1125 C16H17N5O3S 400MHz (DMSO d6) 0.85(6H, d, J = 6.8 Hz), 1.93- 2.00(1H, m), 2.66(3H, s),3.96(2H, d, J = 6.0 Hz), 7.48(1H, d, J = 8.8 Hz), 8.18(1H, dd, J = 2.4,8.8 Hz), 8.27(1H, d, J = 2.4 Hz), 9.79(1H, s), 13.41(1H, s) 26 26 11.35374.1287 374.1281 C17H19N5O3S 400 MHz (DMSO d6) 0.83(9H, s), 2.66(3H,s), 3.83(2H, s), 7.47(1H, d, J = 8.8 Hz), 8.18(1H, dd, J = 2.4, 8.8 Hz),8.27(1H, d, J = 2.0 Hz), 9.78(1H, s), 13.40(1H, s) 27 27 11.22 372.1104372.1125 C17H17N5O3S 400 MHz (DMSO d6) 1.72-1.97(7H, m), 2.66(3H, s),4.16(2H, d, J = 6.4 Hz), 7.48(1H, d, J = 9.2 Hz), 8.16(1H, dd, J = 2.4,8.8 Hz), 8.28(1H, d, J = 2.4 Hz), 9.75(1H, s), 13.38(1H, s) 28 28 10.99372.1114 372.1125 C17H17N5O3S 400 MHz (DMSO d6) 1.53-1.57(4H, m), 1.66-1.73(2H, m), 1.88-1.93(2H, m), 2.65(3H, s), 5.06- 5.10(1H, m), 7.47(1H,d, J = 8.8 Hz), 8.14(1H, dd, J = 2.4, 8.8 Hz), 8.46(1H, d, J = 2.4 Hz),9.74(1H, s)

Example 29 Synthesis of2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylicacid (Compound No. 29) (Synthesis Method (C))

(1) In the similar manner as in Examples 16 and 24, 1.97 g of ethyl[4-(methoxymethoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylatewas obtained from 4.36 g of 4-bromo-2-nitrophenol.

ESI/MS m/e: 376.0 (M⁺+H, C₁₆H₁₈N₅O₄S)

¹H-NMR (400 MHz, DMCl3) δ(ppm): 1.40 (6H, d, J=7.2 Hz), 2.78 (3H, s),3.48 (3H, s), 4.36 (2H, q, J=6.8 Hz), 5.34 (2H, s), 7.45 (1H, d, J=8.8Hz), 8.05 (1H, dd, J=2.4, 8.8 Hz), 8.44 (1H, d, J=2.4 Hz), 9.17 (1H, s)

(2) A reaction mixture solution was prepared by dissolving 1.97 g ofethyl[4-(methoxymethoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylatein 25 mL of 1,4-dioxane and adding 5.0 mL of 2 M hydrochloric acid washeated under stirring at 60° C. for 8 hours. After the reaction mixturesolution was cooled to room temperature, the precipitated solid wasfiltered to obtain 1.49 g of ethyl2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 332.0 (M⁺+H, C₁₄H₁₄N₅O₃S)

¹H-NMR (400 MHz, DMSO d6) δ(ppm): 1.39 (6H, d, J=7.2 Hz), 2.76 (3H, s),4.35 (2H, q, J=7.2 Hz), 7.22 (1H, d, J=8.4 Hz), 7.39 (1H, s), 7.90 (1H,dd, J=2.4, 8.8 Hz), 8.45 (1H, d, J=2.8 Hz), 9.44 (1H, s)

(3) A solution was prepared by dissolving 13.5 mg of2-methypropan-1,3-diol in 1 mL of tetrahydrofuran and adding 39.3 mg oftriphenylphosphine and 65 μL of a 40% toluene solution of diethylazodicarboxylate to the mixture. After stirring the resultant solutionat room temperature for 30 minutes, a reaction mixture solution preparedby adding 33.1 mg of ethyl2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylateto the solution was stirred at room temperature for 3 hours. After theaddition of water to the reaction mixture solution, extraction wasperformed using ethyl acetate. The organic layer was washed with salineand then dried and concentrated under reduced pressure, followed bypurifying by a conventional method to obtain 67.7 mg of ethyl2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 404.1 (M⁺+H, C₁₈H₂₂N₅O₄S)

(4) A solution was prepared by dissolving 34.1 mg of ethyl2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylatein 1.0 mL of a mixed solution of tetrahydrofuran/methanol=1/1. Areaction mixture solution prepared by adding 0.2 mL of 2 M sodiumhydroxide aqueous solution to the solution was stirred at roomtemperature for 3 hours. After the addition of 0.2 mL of 2 Mhydrochloric acid to the reaction mixture solution under stirring, 3 mLof water was added and extraction was performed using 4 mL of ethylacetate. The organic layer was concentrated, followed by purifying by aconventional method to obtain 15.4 mg of2-[4-(3-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylicacid.

¹H-NMR (400 MHz, DMSO d6) δ(ppm): 0.82 (3H, d, J=6.8 Hz), 1.90-1.98 (1H,m), 2.66 (3H, s), 3.25-3.28 (2H, m), 4.04-4.15 (2H, m), 4.62 (1H, m),7.48 (1H, d, J=8.8 Hz), 8.17 (1H, dd, J=2.0, 8.8 Hz), 8.28 (1H, d, J=2.0Hz), 9.80 (1H, s), 13.37 (1H, brs)

-   HPLC Retention Time: 8.23 min.-   Obs Mass (M⁺+H): 376.1074-   Pred Mass (M⁺+H): 376.1074-   Formula (M): C₁₆H₁₇N₅O₄S

Example 30 Synthesis of2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylicacid (Compound No. 30) (Synthesis Method (C))

(1) A solution was prepared by dissolving 33.1 mg of ethyl2-[4-hydroxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylatein 1.0 mL of dimethylformamide. A reaction mixture solution prepared byadding 20.7 mg of potassium carbonate and 16.2 mg of3-bromo-2-methylpropene to the solution was heated under stirring at100° C. for 4 hours. The reaction mixture solution was cooled to roomtemperature and then 3 mL of water and 4 mL of ethyl acetate were addedunder stirring, followed by concentrating the organic phase to obtain34.1 mg of ethyl4-methyl-2-{4-[(2-methylpropen-1-yl)oxy]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate.(2) A reaction mixture solution prepared by adding 1.0 mL of 35%sulfuric acid aqueous solution to 34.1 mg of ethyl4-methyl-2-{4-[(2-methylpropen-1-yl)oxy]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate was heated under stirring at 80° C.for 4 hours. The reaction mixture solution was cooled to roomtemperature and then 3 mL of water and 4 mL of ethyl acetate were addedunder stirring, and the organic phase was concentrated and purifiedusing a conventional method to obtain 9.9 mg of ethyl2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 404.1 (M⁺+H, C₁₈H₂₂N₅O₄S)

(3) A reaction mixture solution prepared by dissolving 9.9 mg of ethyl2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylatein 1.0 mL of a mixed solution of tetrahydrofuran/methanol=1/1 and adding0.2 mL of 2 M sodium hydroxide aqueous solution was stirred at roomtemperature for 3 hours. After the addition of 0.2 mL of 2 Mhydrochloric acid to the reaction mixture solution under stirring, 3 mLof water was added and extraction was performed using 4 mL of ethylacetate. The organic phase was concentrated and purified by aconventional method to obtain 4.8 mg of2-[4-(2-hydroxy-2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylicacid.

¹H-NMR (400 MHz, DMSO d6) δ(ppm): 1.08 (6H, s), 2.66 (3H, s), 3.96 (2H,s), 4.80 (1H, s), 7.50 (1H, d, J=8.8 Hz), 8.15 (1H, dd, J=2.8, 8.8 Hz),8.31 (1H, d, J=2.4 Hz), 9.90 (1H, s), 13.44 (1H, brs)

-   HPLC Retention Time: 8.29 min.-   Obs Mass (M⁺+H): 376.1073-   Pred Mass (M⁺+H): 376.1074-   Formula (M): C₁₆H₁₇N₅O₄S

Examples 31 and 32

The compounds of compound Nos. 31 and 32 were synthesized in the similarmanner as in Example 24.

HPLC Compound Retention Obs Mass Pred Mass Example No. Time (M+ + H)(M+ + H) Formula(M) 1H NMR 31 31 9.32 332.0824 332.0812 C14H13N5O3S 400MHz (DMSO d6) 1.28(6H, d, J = 6.0 Hz), 4.85- 4.91(1H, m), 7.53(1H, d, J= 8.8 Hz), 8.18(1H, dd, J = 2.0, 8.8 Hz), 8.27(1H, d, J = 2.0 Hz),8.39(1H, s), 9.80(1H, s), 13.60(1H, brs) 32 32 10.23 346.0951 346.0968C15H15N5O3S 400 MHz (DMSO d6) 0.85(6H, d, J = 6.8H), 1.93- 2.01(1H, m),3.96(2H, d, J = 6.4 Hz), 7.49(1H, d, J = 9.2 Hz), 8.20(1H, dd, J = 2.4,8.8 Hz), 8.30(1H, d, J = 2.4 Hz), 8.40(1H, s), 9.78(1H, s), 13.59(1H,brs)

Example 33 Synthesis of4-methyl-2-[4-phenoxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylicacid (Compound No. 33) (Synthesis Method (C))

(1) A mixture was prepared by adding 2.10 g of potassium hydrogencarbonate, 44 mg of palladium chloride (II) and 205 mg of a copperbromide (I) dimethylsulfide complex to 2.20 g of5-bromo-2-fluoronitrobenzene and the resulting mixture was suspended in20 mL of toluene. Subsequently, a reaction mixture solution prepared byadding 2.05 g of ethyl 4-methyl-1,3-thiazole-5-carboxylate, 92.5 μL ofisobutyric acid and 228 mg of di-t-butylcyclohexylphosphine to theresulting suspension was heated at 120° C. for 14 hours under a nitrogenatmosphere. The reaction mixture solution was celite-filtered to removeinsoluble matter and water was added to the filtrate, and extraction wasperformed using ethyl acetate. The organic layer was washed with salineand dried and concentrated under reduced pressure. The resulting crudeproduct was separated and purified by silica gel column chromatographyto obtain 2.28 g of ethyl2-(4-fluoro-3-nitrophenyl)-4-methyl-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 311.0 (M⁺+H, C₁₃H₁₂FN₂O₄S)

(2) A reaction mixture solution prepared by suspending 931 mg of ethyl2-(4-fluoro-3-nitrophenyl)-4-methyl-1,3-thiazole-5-carboxylate, 339 mgof phenol and 622 mg of potassium carbonate in 15 mL ofdimethylformamide was heated at 100° C. for 14 hours under a nitrogenatmosphere. The reaction mixture solution was cooled to roomtemperature, water was added and extraction was performed using ethylacetate. The organic layer was washed with saline and then dried andconcentrated under reduced pressure. The resulting crude product wasseparated and purified by silica gel column chromatography to obtain1.14 g of ethyl2-(3-nitro-4-phenoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 385.0 (M⁺+H, C₁₉H₁₇N₂O₅S)

(3) A reaction mixture solution prepared by suspending 1.14 g of ethyl2-(3-nitro-4-phenoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate in 15 mLof ethanol and adding 300 mg of palladium/carbon (10 wt %) was stirredat room temperature for 14 hours under a hydrogen atmosphere. Thereaction mixture solution was celite-filtered and the filtrate wasconcentrated under reduced pressure to obtain 1.05 g of ethyl2-(3-amino-4-phenoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate.

ESI/MS m/e: 355.1 (M⁺+H, C₁₉H₁₉N₂O₃S)

(4) In the similar manner as in Example 24, 458 mg of4-methyl-2-[4-phenoxy-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylicacid was obtained using 1.05 g of ethyl2-(3-amino-4-phenoxyphenyl)-4-methyl-1,3-thiazole-5-carboxylate.

¹H-NMR (400 MHz, DMSO d6) δ(ppm): 2.67 (3H, s), 7.11-7.29 (4H, m),7.43-7.48 (2H, m), 8.15 (1H, dd, J=2.4, 8.8 Hz), 8.42 (1H, d, J=2.0 Hz),9.97 (1H, s),

-   HPLC Retention Time: 10.79 min.-   Obs Mass (M⁺+H): 380.0803-   Pred Mass (M⁺+H): 380.0812-   Formula (M): C₁₈H₁₃N₅O₃S

Examples 34 to 48

The compounds of Compound Nos. 34 to 48 were synthesized in the similarmanner as in Example 33.

Com- HPLC Ex- pound Retention Obs Mass Pred Mass ample No. Time (M+ + H)(M+ + H) Formula(M) 1H NMR 34 34 10.67 398.0722 398.0718 C18H12FN5O3S400 MHz (DMSO d6) 2.67(3H, s), 7.11(1H, d, J = 8.8 Hz), 7.30-7.48(4H,m), 8.16(1H, dd, J = 2.4, 8.8 Hz), 8.44(1H, d, J = 2.4 Hz), 9.99(1H, s)35 35 10.80 410.0908 410.0918 C19H15N5O4S 400 MHz (DMSO d6) 2.68(3H, s),3.71(3H, s), 6.90(1H, d, J = 8.8 Hz), 7.03-7.31 (4H, m), 8.10(1H, dd, J= 2.4, 8.8 Hz), 8.38(1H, d, J = 2.8 Hz), 9.94(1H, s) 36 36 10.63416.0620 416.0623 C18H11F2N5O3S 400 MHz (DMSO d6) 2.66(3H, s), 7.18(1H,d, J = 8.8 Hz), 7.35-7.45 (3H, m), 8.18(1H, dd, J = 2.0, 8.8 Hz),8.43(1H, d, J = 2.4 Hz), 10.00(1H, s) 37 37 10.87 398.0717 398.0718C18H12FN5O3S 300 MHz (DMSO d6) 2.68(3H, s), 7.02-7.18 (3H, m), 7.27(1H,d, J = 8.7 Hz), 7.50(1H, q, J = 8.1 Hz), 8.18(1H, dd, J = 2.1, 8.7 Hz),8.43(1H, d, J = 2.1 Hz), 9.98(1H, s) 38 38 11.49 394.0958 394.0968C19H15N5O3S 300 MHz (DMSO d6) 2.31(3H, s), 2.68(3H, s), 6.97-7.16 (4H,m), 7.32-7.37(1H, m), 8.16(1H, dd, J = 2.7, 9.0 Hz), 8.41(1H, d, J = 2.1Hz), 9.98(1H, s) 39 39 11.17 414.0421 414.0422 C18H12ClN5O3S 300 MHz(DMSO d6) 2.68(3H, s), 7.02(1H, d, J = 8.7 Hz), 7.14-7.81 (4H, m),8.18(1H, d, J = 8.4 Hz), 8.46(1H, s), 9.98(1H, s), 13.37(1H, brs) 40 4011.56 412.0884 412.0874 C19H14FN5O3S 300 MHz (DMSO d6) 2.23(3H, s),2.68(3H, s), 7.07-7.28 (4H, m), 8.15(1H, dd, J = 2.7, 8.7 Hz), 8.42(1H,d, J = 2.1 Hz), 9.99(1H, s) 41 41 11.39 412.0873 412.0874 C19H14FN5O3S300 MHz (DMSO d6) 2.21(3H, s), 2.68(3H, s), 6.92(1H, d, J = 8.7 Hz),7.15-7.30 (3H, m), 8.13(1H, dd, J = 2.1, 9.0 Hz), 8.42(1H, d, J = 2.1Hz), 10.00(1H, s) 42 42 10.83 416.0607 416.0623 C18H11F2N5O3S 300 MHz(DMSO d6) 2.68(3H, s), 7.13-7.61 (4H, m), 8.15(1H, dd, J = 2.1, 9.0 Hz),8.44(1H, d, J = 2.1 Hz), 10.01(1H, s) 43 43 10.80 428.0819 428.0823C19H14FN5O4S 300 MHz (DMSO d6) 2.67(3H, s), 3.77(3H, s), 6.97-7.10 (3H,m), 7.32-7.40(1H, m), 8.10(1H, dd, J = 2.1, 8.7 Hz), 8.40(1H, d, J = 2.1Hz), 9.92(1H, s) 44 44 11.36 394.0973 394.0968 C19H15N5O3S 300 MHz (DMSOd6) 2.12(3H, s), 2.65(3H, s), 6.91(1H, d, J = 8.7 Hz), 7.11-738 (4H, m),8.10(1H, dd, J = 2.1, 9.0 Hz), 8.39(1H, d, J = 2.1 Hz), 9.98(1H, s) 4545 11.54 394.0963 394.0968 C19H15N5O3S 300 MHz (DMSO d6) 2.11(3H, s),2.66(3H, s), 7.07-7.28 (5H, m), 8.11(1H, dd, J = 2.1, 8.7 Hz), 8.37(1H,d, J = 2.1 Hz), 9.98(1H, s) 46 46 11.58 412.0876 412.0874 C19H14FN5O3S300 MHz (DMSO d6) 2.31(3H, s), 2.67(3H, s), 6.86-6.97 (3H, m), 7.27(1H,d, J = 9.0 Hz), 8.16(1H, dd, J = 2.1, 8.7 Hz), 8.41(1H, d, J = 2.1 Hz),9.92(1H, s) 47 47 10.76 416.0629 416.0623 C18H11F2N5O3S 300 MHz (DMSOd6) 2.67(3H, s), 7.07-7.40 (4H, m), 8.11(1H, dd, J = 2.4, 8.7 Hz),8.44(1H, d, J = 2.1 Hz), 9.71(1H, s) 48 48 11.36 412.0871 412.0874C19H14FN5O3S 300 MHz (DMSO d6) 2.30(3H, s), 2.68(3H, s), 7.11-7.36 (4H,m ), 8.16(1H, dd, J = 2.1, 8.7 Hz), 8.44(1H, d, J = 2.1 Hz), 9.99(1H, s)

Example 49 Synthesis of4-methl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylicacid (Compound No. 49) (Synthesis Method (D))

(1) A reaction mixture solution prepared by suspending 155.2 mg of ethyl2-[4-fluoro-3-nitrophenyl]-4-methyl-1,3-thiazole-5-carboxylate and 244.4mg of cesium carbonate in 1.5 mL of N,N-dimethylformamide and adding49.6 mg of 2-methylpropylthiol was heated under stirring at 80° C. for 5hours under a nitrogen atmosphere. The reaction mixture solution wascooled to room temperature, 3 mL of water was added and extraction wasperformed using ethyl acetate. The organic layer was concentrated underreduced pressure to obtain a crude product of ethyl2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylate.(2) The crude product of ethyl2-[4-(2-methylpropylthio)-3-nitropheny]-4-methyl-1,3-thiazole-5-carboxylateobtained above was reduced using palladium carbon under a hydrogenatmosphere to obtain ethyl2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.(3) A reaction mixture solution prepared by suspending ethyl2-[3-amino-4-(2-methylpropylthio)phenyl]-4-methyl-1,3-thiazole-5-carboxylateobtained above in 2.0 mL of acetic acid and adding 65 mg of sodium azideand 148 mg of triethyl ortho formate was heated at 70° C. for 5 hoursunder a nitrogen atmosphere. The reaction mixture solution was cooled toroom temperature, water was added and extraction was performed usingethyl acetate. The organic layer was washed with saline and then driedand concentrated under reduce pressure, followed by purifying by aconventional method to obtain 123 mg of ethyl4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylate.(4) A reaction mixture solution prepared by adding 123 mg of ethyl4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carboxylateto 2 mL of a mixed solution of terahydrofuran/methanol=1/1 and adding0.5 mL of 2 M sodium hydroxide aqueous solution was stirred at roomtemperature for 3 hours. After the addition of 0.5 mL of 2 Mhydrochloric acid to the reaction mixture solution under stirring, 3 mLof water was added and extraction was performed using ethyl acetate. Theorganic phase was concentrated, followed by purifying by a conventionalmethod to obtain 67.9 mg of4-methyl-2-{4-[(2-methylpropyl)sulfanyl]-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl}-1,3-thiazole-5-carbxylicacid.

¹H-NMR (400 MHz, DMSO d6) δ(ppm): 0.91 (6H, d, J=8.0 Hz), 1.75 (1H,septet, J=8.0 Hz), 2.66 (3H, s), 2.93 (2H, d, J=8.0 Hz), 7.78 (1H, d,J=8.0 Hz), 8.17-8.19 (2H, m), 9.89 (1H, s), 13.48 (1H, brs)

-   HPLC Retention Time: 11.19 min.-   Obs Mass (M⁺+H): 376.0887-   Pred Mass (M⁺+H): 376.0896-   Formula (M): C₁₆H₁₇N₅O₂S₂

Examples 50 and 51

The compounds of Compound Nos. 50 and 51 were synthesized in the similarmanner as in Example 49.

HPLC Compound Retention Obs Mass Pred Mass Example No. Time (M+ + H)(M+ + H) Formula(M) 1H NMR 50 50 10.45 362.0736 362.0740 C15H15N5O2S2400 MHz (DMSO d6) 1.15(6H, d, J = 6.8 Hz), 2.62(3H, s), 3.56-3.63(1H,m), 7.80(1H, d, J = 8.4 Hz), 8.14-8.18(2H, m), 9.82(1H, s) 51 51 11.83410.0730 410.0740 C19H15N5O2S2 400 MHz (DMSO d6) 2.33(3H, s), 2.65(3H,s), 7.18-7.37 (5H, m), 8.10(1H, d, J = 8.8 Hz), 8.26(1H, s), 9.96(1H,s), 13.49(1H, brs)

Example 52 Synthesis of4-methyl-2-[4-(N,N-diethylamino)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylicacid (Compound No. 52)

(1) A reaction mixture solution prepared by suspending 220 mg of5-bromo-2-fluoronitrobenzene and 276 mg of potassium carbonate in 2 mLof N,N-dimethylformamide and adding 88 mg of N,N-diethylamine was heatedunder stirring at 40° C. for 14 hours under a nitrogen atmosphere. Thereaction mixture solution was cooled to room temperature, 3 mL of waterwas added and extraction was performed using ethyl acetate. The organiclayer was concentrated under reduced pressure to obtain a crude productof 5-bromo-2-(N,N-diethylamino)nitrobenzene.(2) A suspension was prepared by adding 210.3 mg of potassium hydrogencarbonate, 5.3 mg of palladium chloride (II), 49.3 mg of a copperbromide (I) dimethylsulfide complex and 21.5 mg of2-(di-t-butylphosphino)biphenyl to the crude product of5-bromo-2-(N,N-diethylamino) nitrobenzene obtained above, followed bysuspending the mixture in 2 mL of toluene. A reaction mixture solutionprepared by adding 188.3 mg of ethyl 4-methyl-1,3-thiazole-5-carboxylateand 10.6 mg of isobutyric acid to the suspension was heated at 130° C.for 13 hours under a nitrogen atmosphere. Water was added to thereaction mixture solution and extraction was performed using ethylacetate. The organic layer was concentrated under reduced pressure andthen the resulting crude product was separated and purified by silicagel column chromatography to obtain 256.1 mg of ethyl2-[4-(N,N-diethylamino)-3-nitrophenyl]-4-methyl-1,3-thiazole-5-carboxylate.(3) Ethyl2-[4-(N,N-diethylamino)-3-nitrophenyl]-4-methyl-1,3-thiazole-5-carboxylateobtained above was reduced by palladium carbon under a hydrogenatmosphere to obtain ethyl 2-[3-amino-4-(N,N-diethylamino)phenyl]-4-methyl-1,3-thiazole-5-carboxylate.(4) A reaction mixture solution prepared by suspending ethyl2-[3-amino-4-(N,N-diethylamino)phenyl]-4-methyl-1,3-thiazole-5-carboxylateobtained above in 3.0 mL of acetic acid and adding 91.6 mg of sodiumazide and 209.2 mg of triethyl ortho formate was heated at 70° C. for 5hours under a nitrogen atmosphere. The reaction mixture solution wascooled to room temperature, water and a saturated sodium hydrogencarbonate aqueous solution were added, and extraction was performedusing ethyl acetate. The organic layer was washed with saline and thendried and concentrated under reduced pressure, followed by purifying bya conventional method to obtain 295.9 mg of ethyl2-[4-(N,N-diethylamino)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylate.(5) A reaction mixture solution prepared by dissolving 295.9 mg of ethyl2-[4-(N,N-diethylamino)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylateobtained above in 3 mL of a mixed solution oftetrahydrofuran/methanol=1/1 and adding 2.0 mL of 2 M sodium hydroxideaqueous solution was stirred at room temperature for 2 hours. After theaddition of 2.0 mL of 2 M hydrochloric acid to the reaction mixturesolution, the mixture was purified by a conventional method to obtain199.9 mg of4-methyl-2-[4-(N,N-diethylamino)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylicacid.

¹H-NMR (400 MHz, DMSO d6) δ(ppm): 0.85 (6H, d, J=8.0 Hz), 2.64 (3H, s),2.80 (4H, d, J=8.0 Hz), 7.41 (1H, d, J=8.0 Hz), 8.02 (1H, d, J=4.0 Hz),8.08 (1H, dd, J=8.0, 4.0 Hz), 9.82 (1H, s)

-   HPLC Retention Time: 10.50 min.-   Obs Mass (M⁺+H): 359.1289-   Pred Mass (M⁺+H): 359.1285-   Formula (M): C₁₆H₁₈N₆O₂S

Example 53

The compound of Compound No. 53 was synthesized in the similar manner asin Example 52.

HPLC Compound Retention Obs Mass Pred Mass Example No. Time (M+ + H)(M+ + H) Formula(M) 1H NMR 53 53 9.75 357.1124 357.1128 C16H16N6O2S 400MHz (DMSO d6) 1.75(4H, s), 2.61(3H, s), 2.81(4H, s), 7.01(1H, d, J = 9.2Hz), 7.83(1H, s), 7.98(1H, d, J = 8.8 Hz), 9.80(1H, s)

Example 54

The xanthine oxidase inhibitory activity was measured for the compoundssynthesized according to the above Examples.

(1) Preparation of Test Compounds

Test compound was dissolved in DMSO (manufactured by Sigma Co.) toprepare a 20 mM solution. The solution was adjusted to an optimalconcentration and used for the testing.

(2) Measurement Method

The evaluation of the xanthine oxidase inhibitory activity of thecompounds of the present invention was conducted by the method describedin the reference (Method Enzymatic Analysis, 1, 521-522, 1974) withpartial modification. This evaluation was carried out by measuringoxidase-type xanthine oxidoreductase acrivity. Concretely, a xanthine(manufactured by Sigma Co.) solution was prepared at 10 mM using a 20 mMsodium hydroxide solution and then mixed with 100 mM phosphate buffer toadjusted to 30 μM. 75 μL of the solution was added to each well of the96-well plate. The test compound diluted with DMSO at 100 times of afinal concentration was added to each well at 1.5 μL per well. Aftermixing the plate, absorbance at 290 nm was measured by a microplatereader SPECTRA MAX Plus 384 (manufactured by Molecular Devices, LLC).Subsequently, oxidase-type xanthine oxidoreductase (from buttermilk,manufactured by Calbiochem Novabiochem Corp.) was prepared at 30.6 mU/mLusing a 100 mM phosphate buffer solution and added to each well at 73.5μL per well. Immediately after mixing, the change of absorbance at 290nm was measured for 5 minutes. The enzyme activity of DMSO solutionwithout test compound was used as 100% control, and the inhibitory rateof the test compounds was calculated. Fifty percent inhibitoryconcentration of the test compounds on the oxidase-type xanthineoxidoreductase activity was calculated by fitting to the dose-responsecurve.

The results are shown in the following table. Note that the symbols (+,++, +++) in the table represent inhibitory activity values as shownbelow.

10.0 nM≦IC₅₀: +

5.0 nM≦IC₅₀<10.0 nM: ++

1.0 nM≦IC₅₀<5.0 nM: +++

Compound Inhibitor No. Activity 1 +++ 2 ++ 3 ++ 4 ++ 5 ++ 6 ++ 7 + 8 + 9+++ 10 ++ 11 +++ 12 +++ 13 +++ 14 +++ 15 + 16 +++ 17 +++ 18 +++ 19 +++20 +++ 21 +++ 22 + 23 + 24 +++ 25 +++ 26 +++ 27 +++ 28 +++ 29 +++ 30 +++31 +++ 32 +++ 33 +++ 34 +++ 35 +++ 36 +++ 37 +++ 38 +++ 39 +++ 40 +++ 41+++ 42 +++ 43 +++ 44 +++ 45 +++ 46 +++ 47 +++ 48 +++ 49 +++ 50 +++ 51+++ 52 +++ 53 +++

Example 55 Hypouricemic Effect (Normal Rats)

The hypouricemic effect was confirmed for the compounds of compound No.17, 24, 25 and 26. A test compound suspended in a 0.5% methylcellulosesolution was administered to 8 to 9 week-old Sprague-Dawley male rats(Japan Charles River Co.) by oral gavage administration using a feedingneedle. After the blood was collected from the tail vein at 2 hoursafter administration, the plasma was separated. The level of uric acidin the blood sample was measured by uricase method using an absorptionspectrometer as well as a uric acid determination kit (L type Wako UA F:Wako Pure Chemical Industries, Ltd.). The percentage of hypouricemiceffect was determined by the following expression:

Percentage of hypouricemic effect (%)=(Level of uric acid of the controlanimal−Level of uric acid of the test compound-administeredanimal)×100/Level of uric acid of the control animal.

All of compounds of compound No. 17, 24, 25 and 26 showed a hypouricemiceffect of 50% or more at the dose of 10 mg/kg.

Further, compounds of compound No. 24, 25 and 26 showed a hypouricemiceffect of 50% or more even at the dose of 1 mg/kg.

From the above results, it was shown that the compounds of the presentinvention have a potent hypouricemic effect.

Example 56

Prolonged Hypouricemic Effect (Normal Rats)

By using compounds of compound No. 17, 25 and 26, a test compound wasadministered to Sprague-Dawley male rats in the similar manner as inExample 55. After the blood was collected from the tail vein 24 hoursafter administration, the plasma was separated. The level of uric acidin the blood was measured by an uricase method using an absorptionspectrometer and a uric acid determination kit (L type Wako UA F: WakoPure Chemical Industries, Ltd.). The percentage of hypouricemic effectwas determined by the following expression:

Percentage of hypouricemic effect (%)=(Level of uric acid of the controlanimal−Level of uric acid of the test compound-administeredanimal)×100/Level of uric acid of the control animal.

All of the compounds of compound No. 17, 25 and 26 showed a hypouricemiceffect of 50% or more in 24 hours after administration at the dose of 10mg/kg.

Further, all of the compounds of compound No. 25 and 26 showed ahypouricemic effect of 40% or more in 24 hours after administration evenat the dose of 3 mg/kg.

From the above results, the compounds of the present invention have aprolonged hypouricemic effect over a long period of time.

Example 57

Hypouricemic Effect (Hyperuricemic Beagle Dogs)

The hypouricemic effect was confirmed for the compounds of compound No.25 in oxonic acid-induced hyperuricmic beagle dog. A test compoundsuspended in a 0.5% methylcellulose solution was administered to beagledog (Kitayama labes) by oral gavage administration. Potassium oxonate(50 mg/kg) was subcutaneously administrated before and 4 hours aftercompound administration. After the blood was collected from the cephalicvein at 8 hours after administration, the plasma was separated. Thelevel of uric acid in the plasma sample was measured by LC-MS/MS methodand the percentage of hypouricemic effect was determined by thefollowing expression:

Percentage of hypouricemic effect (%)=(Level of uric acid of the controlanimal−Level of uric acid of the test compound-administeredanimal)×100/Level of uric acid of the control animal.

Compounds of compound No. 25 showed a hypouricemic effect at the dose of10 mg/kg.

From the above results, it was shown that the compounds of the presentinvention have a potent hypouricemic effect in beagle dog.

Example 58

Prolonged Inhibitory Effect of Xanthine Oxidase in Tissue and Plasma.

For “xanthine oxidase” in the present invention, as far as this example,oxidative reaction catalyzing activities which are brought byoxidase-type xanthine oxidoreductase solely and by both oxidase-type anddehydrogenase-type xanthine oxidoreductase are distinguished. The formeris “XO activity” and the latter is “XOR activity”. In “tissue XOactivity”, “plasma XO activity”, “tissue XOR activity inhibition”,“tissue XOR activity inhibition” and the like, “XO activity” and “XORactivity” have the same meanings as defined above. The tissue includesliver, kidney, adipose tissue, intestine and vessel. In addition,percentage of XO activity inhibition and that of XO activity inhibitionin same sample are thought to be similar, according to the resultsbelow.

The inhibitory effect of tissue XO activity tissue XOR activity andplasma XO activity was confirmed for the compounds of compound No. 17,25 and 26. A test compound suspended in a 0.5% methylcellulose solutionwas administered to 7 to 9 week-old Sprague-Dawley male rats (JapanCharles River Co.) by oral gavage administration using a feeding needle.The blood was collected from the abdominal vein and tissue was collectedat 24 or 27 hours after administration. Plasma sample was prepared bycentrifugation.

Tissue XO activity, tissue XOR activity and plasma XO activity weremeasured by the pterin-based assay which utilizes the reaction thatpterin is oxidized by each type of xanthine oxidoreductase to producefluorescent isoxanthopterin. In brief, frozen tissues were homogenizedwith potassium phosphate buffer, pH 7.4, containing 1 mMethylenediaminetetraacetic acid (EDTA) and protease inhibitors toprepare tissue concentration as follow (liver: 25 mg/mL, kidney: 25mg/mL, intestine: 5 mg/mL, adipose tissue: 5 mg/mL, vessel: 30 mg/mL).Then the homogenates were centrifuged 12,000 rpm for 15 min at 4° C.When measured XO activity, the supernatant of tissue and plasma wererespectively co-incubated with 50 μM pterin solution at 37° C. Whenmeasured XOR activity, the supernatant of tissue homogenate wasco-incubated with 50 μM pterin and 50 μM methylene blue solution at 37°C. As a control, oxidase-type xanthine oxidoreductase (from buttermilk,manufactured by Calbiochem Novabiochem Corp.) was also incubated withpterin solution in the same manner. XO activity and XOR activity of thesamples were determined from fluorescence intensity which normalized bythe intensity value of control and protein concentration.

The percentage of XO activity inhibition and XOR activity inhibitionwere determined by the following expression:

Percentage of XO or XOR activity inhibition (%)=(XO or XOR activity ofthe control animal−XO or XOR activity of the test compound-administeredanimal)×100/XO or XOR activity of the control animal.

Liver and kidney XO activities and plasma XO activity 27 hours aftercompound 17, 25 and 26 administration are shown in the table below.

% inhibition of tissue and Plasma XO activity (27 hours afteradministration) % of inhibition (vs. vehicle) compound 17 25 26 Dose(mg/kg) 1 10 1 10 1 10 Liver ≧80% ≧80% ≧80% ≧80% ≧80% ≧80% Kidney ≧60%≧70% ≧60% ≧70% ≧60% ≧70% Plasma ≧25% ≧40% ≧25% ≧40% ≧25% ≧40%Intestine, adipose tissue and vessel XOR activities 24 hours aftercompounds 25 and 26 administration are shown in the table below.

% inhibition of of tissue XO and XOR activity (At dissection 24 hoursafter administration) % of inhibition (vs. vehicle) Dosage Compound 25(mg/kg) Activity 1 10 Liver XOR ≧80% ≧80% Liver XO ≧80% ≧80% Kidney XOR≧60% ≧70% Kidney XO ≧60% ≧70% Intestines XOR ≧60% ≧80% Adipose XOR ≧30%≧60% Blood vessel XOR ≧25% ≧40%

% inhibition of tissue XOR activity (At dissection 24 hours afteradministration) % of inhibition (vs. vehicle) Compound 26 Dosage (mg/kg)1 10 Blood vessel ≧30% ≧50%

All of compounds of compound No. 17, 25 and 26 inhibited 80% or more XOactivity 27 hours after drug administration compared to the controlanimal at the dose of 10 mg/kg in liver.

All of compounds of compound No. 17, 25 and 26 inhibited 70% or more XOactivity 27 hours after drug administration compared to the controlanimal at the dose of 10 mg/kg in kidney.

All of compounds of compound No. 17, 25 and 26 inhibited 40% or more XOactivity 27 hours after drug administration compared to the controlanimal at the dose of 10 mg/kg in plasma.

In addition, compound No. 25 inhibited 80% or more of each XOR activityand XO activity 24 hours after drug administration compared to thecontrol animal at the dose of 10 mg/kg in liver.

Compound No. 25 inhibited 70% or more of each XOR activity and XOactivity 24 hours after drug administration compared to the controlanimal at the dose of 10 mg/kg in kidney.

In addition, compound No. 25 inhibited 80% or more XOR activity 24 hoursafter drug administration compared to the control animal at the dose of10 mg/kg in intestine.

Compound No. 25 inhibited 60% or more XOR activity 24 hours after drugadministration compared to the control animal at the dose of 10 mg/kg inadipose tissue.

Compound No. 25 inhibited 40% or more XOR activity 24 hours after drugadministration compared to the control animal at the dose of 10 mg/kg invessel.

Compound No. 26 inhibited 50% or more XOR activity 24 hours after drugadministration compared to the control animal at the dose of 10 mg/kg inblood vessel.

Further, all of compounds of compound No. 17, 25 and 26 inhibited 80% ormore XO activity 27 hours after drug administration compared to thecontrol animal even at the dose of 1 mg/kg in liver.

All of compounds of compound No. 17, 25 and 26 inhibited 60% or more XOactivity 27 hours after drug administration compared to the controlanimal even at the dose of 1 mg/kg in kidney.

All of compounds of compound No. 17, 25 and 26 inhibited 25% or more XOactivity 27 hours after drug administration compared to the controlanimal even at the dose of 1 mg/kg in plasma.

In addition, compound No. 25 inhibited 80% or more of each XOR activityand XO activity 24 hours after drug administration compared to thecontrol animal at the dose of 1 mg/kg in liver.

Compound No. 25 inhibited 60% or more of each XOR activity and XOactivity 24 hours after drug administration compared to the controlanimal at the dose of 1 mg/kg in kidney.

Compound No. 25 inhibited 60% or more XOR activity 24 hours after drugadministration compared to the control animal at the dose of 1 mg/kg inintestine.

Compound No. 25 inhibited 30% or more XOR activity 24 hours after drugadministration compared to the control animal at the dose of 1 mg/kg inadipose tissue.

Compound No. 25 inhibited 25% or more XOR activity 24 hours after drugadministration compared to the control animal at the dose of 1 mg/kg inblood vessel.

Compound No. 26 inhibited 30% or more XOR activity 24 hours after drugadministration compared to the control animal at the dose of 1 mg/kg inblood vessel.

These results show that a compound of the present invention haspersistent inhibitory effect for long period on XO and XOR activity ineach tissue.

INDUSTRIAL APPLICABILITY

A compound represented by the formula (I) of the present invention and apharmaceutically acceptable salt thereof can be used as a xanthineoxidase inhibitory drug, a drug for improving vascular endothelialfunction, a therapeutic agent or a prophylactic agent for diseasesassociated with xanthine oxidase such as gout, hyperuricemia, tumorlysis syndrome, urinary calculi, hypertension, dyslipidemia, diabetes,kidney diseases such as diabetic nephropathy, respiratory diseases suchas chronic obstructive pulmonary disease, inflammatory bowel disease andautoimmune disease, and diseases associated with a vascular endothelialfunctional disorder such as arteriosclerosis, myocardial infarction,cerebral infarction and cerebrovascular dementia.

1. A xanthine oxidase inhibitor comprising a compound represented by thefollowing formula (I) or a pharmaceutically acceptable salt thereof asan active ingredient:

[wherein, R₁ represents OR, NRR′ which may form a ring or SR, in which Rand R′ independently represent a hydrogen atom, an alkyl group having 1to 8 carbon atoms optionally substituted with one or a plurality ofalkoxy groups having 1 to 8 carbon atoms, halogen atoms or hydroxylgroups, or an aryl group optionally substituted with one or a pluralityof alkyl groups having 1 to 8 carbon atoms, alkoxy groups having 1 to 8carbon atoms or halogen atoms, or a heteroaryl group optionallysubstituted with one or a plurality of alkyl groups having 1 to 8 carbonatoms, alkoxy groups having 1 to 8 carbon atoms or halogen atoms, R₂represents a hydrogen atom or an alkyl group having 1 to 8 carbon atoms,X₁, X₂ and X₃ are independently CR₃ or a nitrogen atom, or X₁ is CR₃ ora nitrogen atom, and X₂ and X₃ together form a benzene ring, in which R₃is a hydrogen atom or an alkyl group having 1 to 8 carbon atoms.]
 2. Atherapeutic agent or a prophylactic agent for diseases associated withxanthine oxidase, which contains a compound represented by the formula(I) or a pharmaceutically acceptable salt thereof as an activeingredient.
 3. The therapeutic agent or the prophylactic agent accordingto claim 2, wherein the disease is gout, hyperuricemia or tumor lysissyndrome or kidney disease.
 4. An agent for improving vascularendothelial function containing a compound represented by the formula(I) or a pharmaceutically acceptable salt thereof as an activeingredient.
 5. A therapeutic agent or a prophylactic agent for diseasesassociated with vascular endothelial function disorder containing acompound represented by the formula (I) or a pharmaceutically acceptablesalt thereof as an active ingredient.
 6. The therapeutic agent or theprophylactic agent according to claim 5, wherein the disease isarteriosclerosis, myocardial infarction, cerebral infarction orcerebrovascular dementia.
 7. The agent according to claim 1, wherein R₁is OR.
 8. The agent according to claim 1, wherein R₁ is SR.
 9. The agentaccording to, wherein R₁ is NRR′ which may form a ring.
 10. The agentaccording to claim 1, wherein R and R′ are independently an alkyl grouphaving 1 to 8 carbon atoms optionally substituted with one or aplurality of alkoxy groups having 1 to 8 carbon atoms, halogen atoms orhydroxyl groups, or an aryl group optionally substituted with one or aplurality of alkyl groups having 1 to 8 carbon atoms, alkoxy groupshaving 1 to 8 carbon atoms or halogen atoms.
 11. The agent according toclaim 10, wherein R and R′ are independently an alkyl group having 1 to8 carbon atoms optionally substituted with one or a plurality of alkoxygroups having 1 to 8 carbon atoms, halogen atoms or hydroxyl groups. 12.The agent according to claim 11, wherein R₁ is OR or SR, and R is anisopropyl group, a isobutyl group or a neopentyl group.
 13. The agentaccording to claim 1, wherein R₂ is a hydrogen atom or an alkyl grouphaving 1 to 3 carbon atoms.
 14. The agent according to claim 13, whereinR₂ is a methyl group.
 15. The agent according to claim 1, wherein X₁, X₂and X₃ are independently CR₃ or a nitrogen atom.
 16. The agent accordingto claim 15, wherein X₁ is a nitrogen atom, X₂ is CR₃ or a nitrogen atomand X₃ is CR₃.
 17. The agent according to claim 1, wherein R₃ is ahydrogen atom.
 18. The agent according to claim 1, wherein a compoundrepresented by the formula (I) is4-methyl-2-[4-(2-methylpropoxy)-3-(1H-1,2,3-triazol-1-yl)phenyl]-1,3-thiazole-5-carboxylicacid,4-methyl-2-[4-(2-methylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-1,3-thiazole-5-carboxylicacid or2-[4-(2,2-dimethylpropoxy)-3-(1H-1,2,3,4-tetrazol-1-yl)phenyl]-4-methyl-1,3-thiazole-5-carboxylicacid.